Neoplasms

Blood and Lymph Conditions

All Conditions

Symptoms and General Pathology

Rare Diseases

Leukemia

Leukemia, Myeloid

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Philadelphia Chromosome

Neoplasm, Residual

Neoplasms by Histologic Type

Hematologic Diseases

Myeloproliferative Disorders

Bone Marrow Diseases

Chronic Disease

Disease Attributes

Myeloid Leukemia

Chronic Graft Versus Host Disease

Chronic Myeloid Leukemia

Chronic Myeloproliferative Disorders

All Drugs and Chemicals

Anti-Infective Agents

Antineoplastic Agents

Amino Acids

Tyrosine Kinase Inhibitors

Interferon-alpha

Peginterferon alfa-2a

Interferon alpha-2

Antiviral Agents

Tyrosine

PEG-IFNá-2a (Pegasys) 45 mcg subcutaneously as single weekly dose.

45 mcg given subcutaneously as a single weekly dose for 24 months.

PEG-IFNá-2a

Alfonso Quintas-Cardama, MD

The goal of this clinical research study is to learn if adding pegylated interferon-alfa 2a (Pegasys) to the TKI that you are already receiving can help to control CML. The safety of this treatment combination will also be studied.

Pegasys is a form of the drug interferon. It is designed to help the body's immune system to fight infections. It may also affect the body's response to cancer.

A TKI (imatinib mesylate, nilotinib, or dasatinib) is designed to bind to and shut off a protein in tumor cells called Bcr-Abl. Shutting Bcr-Abl off may prevent CML cells from growing, and may cause them to die.

You are already receiving a TKI. This consent form will describe the administration of Pegasys, any tests and procedures that need to be performed while you are receiving Pegasys, and any risks/benefits there may be from receiving Pegasys.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive Pegasys through a needle under the skin 1 time each week while you are on study. You will be taught how to use the study drug at the first visit and will administer it to yourself at all future doses.

You will continue receiving the TKI you are already taking at the dose and frequency you have been receiving it when you began taking part in this study.

Study Visits:

At every study visit, you will be asked about any side effects you may have had and to list any drugs you may be taking.

Every 1-2 weeks for 8 weeks, then every 6-8 weeks after that, blood (about 1-2 teaspoons) will be drawn for routine tests.

Every 3 months for 6 months, then every 6-12 months after that, you will have a complete physical exam, including measurement of your vital signs.

Every 3-6 months for 1 year, you will have a bone marrow aspirate to check the status of the disease and to check for changes in your chromosomes.

Every 3-6 months for 1 year, then every 6-12 months after that, blood (about 1 teaspoon) will be drawn to check the levels of leukemia in the blood.

Length of Study:

You may continue taking Pegasys for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

This is an investigational study. Pegasys is FDA approved and commercially available for the treatment of CML. TKIs (imatinib, nilotinib, and dasatinib) are FDA approved and commercially available for the treatment of CML. The combination of these drugs to treat CML is investigational.

Up to 50 patients will take part in this study. All will be enrolled at MD Anderson.

Pegasys in Patients With Chronic Myeloid Leukemia (CML)

Phase II Study of Pegylated Ifná-2a (Pegasys) in Patients With Chronic Myeloid Leukemia Who Have Minimal Residual Disease While Receiving Therapy With Tyrosine Kinase Inhibitors

Molecular response defined as: major molecular response (MMR) corresponds to a BCR-ABL1/ABL1 ratio of \<=0.01. Complete molecular response (CMR) is defined as undetectable BCR-ABL1 transcripts. Molecular response measured every 3 months (a total of 4 assessments within one year of therapy).

M.D. Anderson Cancer Center

Age, Categorical

Sex: Female, Male

United States

Region of Enrollment

Early termination due to slow accrual, no analysis possible.

Alfonso Quintas-Cardama, MD/Professor, Leukemia

Study terminated due to low accrual. No participants were evaluable for outcome.

Number of Participants Achieved of Major Molecular Response (MMR) or Complete Molecular Response (CMR)

Overall Study

Heart and Blood Diseases

Polycythemia Vera

Polycythemia

Thrombocytosis

Thrombocythemia, Essential

Bone Marrow Neoplasms

Hematologic Neoplasms

Blood Platelet Disorders

Hemostatic Disorders

Blood Coagulation Disorders

Hemorrhagic Disorders

Essential Thrombocythemia

Pharmaceutical Solutions

Interferons

Immunologic Factors

Part A: RG7388 as a single agent; given at a starting dose of 100 mg each day for five days for the first cycle which will be 56 days.

Part B: combination of RG7388 and Pegasys if subject does not achieve at least a PR by the end of 3 cycles of single agent RG7388

RG7388 is supplied as film-coated tablets at dosage strengths of 50 mg, 200 mg, 300mg and 400 mg.

RG7388

PEGASYS is supplied as a clear, sterile solution for subcutaneous (SQ) injection available in prefilled syringes. weekly doses at 45ug subcutaneously

Pegasys

John Mascarenhas, MD

Ronald Hoffman, MD

This research looks at two conditions, Essential Thrombocythemia (ET) and Polycythemia Vera (PV). ET causes people to produce too many blood cells called platelets and PV causes too many platelets and red blood cells to be made. Platelets are particles which circulate in the blood stream and normally prevent bleeding and bruising. Having too many platelets in the blood increases the risk of developing blood clots, which can result in life threatening events like heart attacks and strokes. When the number of red blood cells is increased in PV this will slow the speed of blood flow in the body and increase the risk of developing blood clots.

The purpose of Part A of this study is to test the safety and tolerability of drug RG7388 patients and identify the recommended phase II dose in a single agent dose escalation study. The investigators want to find out what effects, good and/or bad it has on the disease.

The purpose of Part B of this study is to test the safety and tolerability of the combination of RG7388 and Pegylated Interferon Alfa-2a or Pegasys in PV/ET patients from Part A who did not achieve at least a partial response by the end of three cycles of single agent RG7388.

Essential Thrombocythemia (ET) and Polycythemia Vera (PV) have been difficult diseases to treat. RG7388 is a selective inhibitor of the p53-MDM2 binding that frees p53 from negative control and activates the p53 pathway in cancer cells, leading to cell cycle arrest and apoptosis in vitro and in vivo. It has been used to treat solid tumors and Acute Myelogenous Leukemia (AML) in clinical trials. Pegasys is a drug that is the standard of care for patients who have Chronic Hepatitis B (CHB).

RG7388 is a drug that is not yet approved by the Federal Drug Administration (FDA) for the treatment of patients with essential thrombocythemia or polycythemia vera. Pegasys is a drug that is approved by the FDA for the treatment of CHB. The use of RG7388 alone and in combination with Pegasys is experimental.

The Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPNs) are a group of hematopoietic stem cell malignancies that include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). PV and ET can evolve into myelofibrosis, termed post PV/ET MF. ET, PV and PMF have variable tendencies to transform to blast phase disease with a dismal prognosis. JAK2V617F is a point activating mutation resulting in the constitutive activity of the JAK-STAT pathway within hematopoietic cells in approximately 96%, 50%, and 50% of patients with PV, ET, and MF, respectively.

Polycythemia Vera is characterized by an absolute increase in red cell mass. Patients with PV have a median survival if untreated of approximately 18 months from the time of diagnosis and treated of approximately 18 years. PV-related symptoms include headache, weakness, dizziness, epigastric distress, and pruritus. PV-related signs include hypertension, gout, left upper abdominal quadrant pain, high hematocrit, leukocytosis, and thrombocytosis. Major causes of reduced survival include thrombosis (29%), bleeding (7%), evolution to myelofibrosis (3%), transformation to acute leukemia (23%), and solid tumors (16%). PV patients are stratified for risk of thrombosis by age \>60 and history of prior thrombotic events. Therapy for low risk PV includes low dose aspirin and therapeutic phlebotomy to maintain a hematocrit \<45% in a man and 42% in a woman. Cardiovascular risk factor modification such as weight loss, control of hypertension and hypercholesterolemia, and smoking cessation are also important adjunctive approaches to all patients with PV. High risk patients are also treated with cytoreductive therapy in the form of hydroxyurea to further reduce the risk of thrombotic complications.

Essential Thrombocythemia is characterized by persistent isolated thrombocytosis and tendency for arterial and venous thrombosis. A similar pattern of symptoms as noted above with PV are also seen in patients with ET. The median survival of patients with ET is similar to that of age and sex matched cohort and in some patients is limited by thrombotic complications (22%), evolution to MF (10%), and acute leukemia (2%) (Barbui. J Clin Oncol. 2011; 29(23):3179). Risk stratification for occurrence of thrombosis is based on age \>60 years and/or history of thrombosis. Additionally, cardiovascular risk factors and persistent thrombocytosis \>1.5 x 109/L are believed to influence thrombotic risk and leukemic transformation has been shown to be associated with anemia, older age, and leukocytosis. JAK2V617F is present in approximately 50% of cases and helps establish a diagnosis of a clonal thrombocytosis, and has been shown in some studies to predict for a higher risk of thrombosis and potential for transformation to PV. Management is aimed at reducing thrombotic risk with the use of low dose aspirin in low risk patients (no risk factors) and cytoreductive therapy in high risk patients (at least one risk factor). Hydroxyurea, anagrelide, and interferon (IFN) have all been used to maintain a platelet count below 400 x 109/L in patients with a history of thrombosis (secondary prophylaxis). Currently, hydroxyurea is considered standard of care for high risk ET patients based on the results of the PT-1 study which demonstrated superiority of hydroxyurea over anagrelide in arterial thrombosis risk reduction and worsening marrow reticulin fibrosis in patients receiving anagrelide (Harrison N Engl J Med. 2005;353(1):33). Hydroxyurea is associated with a risk of oral and skin ulcers, rash, and unacceptable myelosuppression that can sometimes limit use in patients with ET/PV. Additionally, some patients are unable to achieve adequate control of blood counts at doses below 2000 mg/daily and this has been termed "resistance". Importantly, although a theoretical concern of leukemogenic potential of hydroxyurea exists, based on the mechanism of action of this chemotherapeutic agent, there are no definitive prospective studies clearly documenting an increased risk of leukemic transformation.

More recently, a renewed interest in interferon-α for the treatment of PV as an alternative therapeutic approach has led to the evaluation of pegylated interferon-α 2a (Pegasys, Roche) in several phase II studies. Pegasys has an improved toxicity profile over intron-a and can be self-administered by the patient on a weekly basis. Currently, Pegasys is being evaluated in two large international trials within the myeloproliferative disorder research consortium (MPD-RC). The MPD-RC 111 study is a phase II study intended to evaluate the response by European LeukemiaNet (ELN) criteria in patients with high risk ET/PV who are intolerant or resistant to hydroxyurea therapy treated with Pegasys. In addition, patients with documented JAK2V617F and splanchnic vein thrombosis are also eligible for this clinical trial. MPD-RC 112 is a phase III study for newly diagnosed high risk PV/ET patients in which patients are randomized to either Pegasys or hydroxyurea with a primary endpoint of response rate comparison between the two treatment arms.

The use of intron-a (rIFN-α) and Pegasys has been extensively studied in patients with PV and reported rates of discontinuation in the first year of therapy range from 14-40%. Objective hematologic responses are seen in approximately 80% of treated patients and achievement in complete phlebotomy free state in 60% of PV patients. Trials of Pegasys in the treatment of PV have further demonstrated major molecular responses of 19% and complete eradication of JAK2V617F in 14-24% of patients. Although hematologic remission can often be achieved within months of starting rIFN-α treatment, molecular responses require longer term administration and are rarely seen before completion of 12 months of therapy. Additionally, sustained molecular remissions have been documented in patients that have discontinued therapy for up to 30 months of follow up. In a retrospective review of 118 MPN patients receiving Pegasys throughout multiple MPN centers included 55 PV patients with an ORR of 87% (54% CR, 33% PR) by ELN criteria \[21\]. In this review, the most common non-hematologic toxicities were Grade 1-3 fatigue in 24 patients (20%), Grade 1 liver function test (LFT) elevation in 7 (6%), and Grade 1-2 skin/allergic reaction in 6 (5%). Adverse effects leading to discontinuation were primarily non-hematologic, although one patient (\<1%) discontinued Pegasys therapy due to Grade 2 anemia.

Although the biological mechanism of recombinant IFN in the treatment of PV is not completely understood, evidence to suggest promotion of immunoregulatory cell function, inhibition of angiogenesis, induction of pro-apoptotic gene expression, alteration of the bone marrow microenvironment, suppression of hematopoietic progenitor cells, and increase cycling of hematopoietic stem cells (HSC) has been reported.

In the last several years, oral small molecule tyrosine kinase inhibitors of JAK2 have been tested in both pre-clinical and clinical trials of patients with MPNs including PV/ET. These agents have demonstrated remarkable responses in terms of reduction in splenomegaly and correction of leukocytosis, erythrocytosis, and thrombocytosis. However, mature follow up of PV patients treated with JAK2 inhibitors evaluating reduction in thrombotic risk and evolution to MF is not known. Currently, Ruxolitinib (Jakafi) is being evaluated in a phase III study in patients with high risk PV that are refractory/intolerant to hydroxyurea \[Response trial: NCT01243944\].

The tumor suppressor p53 plays an integral role in the regulation of the cell cycle, apoptosis, DNA repair, and senescence. Fifty percent of cancers are found to have inactivating mutations of p53. Although, inactivating mutations of p53 are uncommon in the chronic phases of MPNs, they increase in frequency in the blast phase of MPNs. The p53 pathway can also be down-regulated in MPN cells that express wild-type p53 through alternative pathways. Over-expression of the ubiquitin ligase murine double minute 2 (MDM2; HDM2 in humans) is a regulator of wild type p53 through a variety of different mechanisms. MDM2 1) promotes proteosomal degradation and 2) inhibits p53 transcription, and 3) inhibits transactivation 4) facilitates export from the nucleus. Inhibition of MDM2 is expected to release the negative regulation of p53 and ultimately promote tumor suppressor function. MDM2 overexpression can be a consequence of gene amplification, increased transcription, and increased translation. It has previously been shown that in primary hematopoietic cells from patients with JAK2V617F PV, reduced expression of p53 is a result of increased La autoantigen expression leading to increased translation of MDM2. It would appear that JAK2V617F induces this ribonucleoprotein and furthermore, La protein expression can be down-regulated by in vitro JAK2 inhibitor treatment. Lu et al demonstrated increased MDM2 expression and reduced p53 levels in JAK2V617F-positive PV CD34+ cells. The physical structure and interaction of p53 and MDM2 is known and has allowed for the development of small molecule inhibitors of MDM2-p53 interaction. Nutlin-3, a small molecule antagonist of MDM2, was shown to inhibit the proliferation of PV CD34+ cells through increased p53 mediated apoptosis. Moreover, in vitro combination of low doses of Pegasys with nutlin-3 resulted in selective and significant inhibition of JAK2V67F-positive CD34+ PV colony formation compared to normal colony formation. Thus, MDM2 appears to be a novel therapeutic target in JAK2V617F-positive PV and ultimately may prove to be most effective when used in combination with Pegasys.

RG7388 is an MDM2-p53 binding cell cycle inhibitor (antiproliferative) and is expected to be myelosuppressive at sufficiently high doses. Nonclinical safety findings with RG7388 that may have potential clinical relevance include thrombocytopenia and neutropenia, as well as general pancytopenia, and effects on liver function parameters.

Clinical experience to date suggests a dose relationship for RG7388 and gastrointestinal AEs with increased incidence of nausea, vomiting, and diarrhea at higher dose levels; gastrointestinal prophylaxis with anti-emetics is recommended. Cytopenias, manifesting as thrombocytopenia and neutropenia, occurring at higher dose levels appear to be related to exposure.

Iancu-Rubin et al have investigated the biological effect of RG7112 (first generation MDM2 inhibitor) induced p53-MDM2 disruption on megakaryopoiesis and platelet production in order to better elucidate the mechanism of treatment associated thrombocytopenia (ASH 2012). Bone marrow derived CD34+ cells exposed to RG7112 for 7 days generated fewer viable cells, fewer CFU-MK colonies as compared to untreated cells. Based on these findings, it would appear that RG7112 impacts megakaryopoiesis by two potential mechanisms: 1) Impairing the ability of CD34+ cells to generate MK precursors due to increased apoptosis; 2) Limiting DNA synthesis and polyploidization during the late stages of MK development due to pharmacological activation of p53. A combination of these two effects may provide an explanation for thrombocytopenia observed in patients receiving this drug and suggests that p53 plays an important role in normal human thrombocytopoiesis.

Study NP27872 is a multi-center, open-label, first-in-human, Phase I dose-escalation study of single agent RG7388, a small molecule MDM2 antagonist, administered orally in patients with advanced malignancies except leukemia. The first patient received RG7388 on 15 November 2011. As of 13 September 2012, 51 patients have been enrolled in the study.

Evaluable PK data is available for 22 patients in Study NP27872. There has been no evidence of significant accumulation (defined as a mean ratio of area under the curve \[AUC\]τ \[on Day 15 or 5\] to AUCinf \[on Day 1\] \> 2) observed in the study thus far, except for one patient who exhibited a long half-life (t½) and consequently had an accumulated drug exposure that increased 5-fold from Day 1 to Day 5. This was possibly due to concomitant controlled-release oxycodone, as opioids are known to cause delayed gastric emptying and decreased intestinal motility. In addition, data from the study demonstrate an approximately linear dose-exposure (Day 1 maximum plasma concentration \[Cmax\]) relationship in RG7388 with moderately high inter-patient variability without an absorption plateau to date.

Macrophage inhibitory cytokine (MIC-1, a secreted protein that is strongly induced by activated p53) serum levels has been used to assess pharmacodynamic (PD) effects in this Phase I study. Analysis of patients on 100 to 800 mg/day of RG7388 showed that the minimum level for p53 induction occurs at a dose of 100 mg/day or a corresponding plasma level of 500 ng/mL of RG7388. Preliminary analysis of PK and safety data showed that there is an apparent PK/PD relationship between an AUC per cycle and Cycle 1 platelet nadir.

At the data cutoff of 13 September 2012, 51 patients with advanced malignancies had received R05503781 in Study NP27872. Fifty patients experienced at least 1 adverse event (AE) and 11 patients experienced at least 1 serious adverse event (SAE).

Thirteen SAEs in patients (white blood cell count decreased, platelet count decreased, 2 cases of neutrophil count decreased, febrile neutropenia, 5 cases of thrombocytopenia, 2 cases of neutropenia, and diarrhea) were considered by the investigator to be probably related to study treatment; 4 SAEs (2 cases of febrile neutropenia, urinary tract infection, and anemia) were considered possibly related; 1 SAE (lung infection) was considered remotely related; and the other 6 SAEs (infection, sciatica, non-cardiac chest pain, dyspnea, wrist fracture, and neutropenia) were considered unrelated. Three patients died due to disease progression.

Eleven patients across all groups and schedules had at least 1 event considered a dose limiting toxicity (DLT): a treatment-related SAE of Grade 3 febrile neutropenia, a treatment-related SAE of Grade 4 febrile neutropenia, a treatment-related SAE of Grade 4 platelet count decreased, 3 cases of treatment-related SAEs of Grade 4 thrombocytopenia, a treatment-related AE of Grade 4 thrombocytopenia, 3 cases of treatment-related AEs of Grade 4 thrombocytopenia, a treatment-related AE of Grade 4 neutropenia, a treatment-related SAE of Grade 4 neutropenia, a treatment-related AE of Grade 3 diarrhea, 2 cases of treatment-related AEs of Grade 3 nausea, and a treatment related AE of Grade 3 vomiting. Six patients experienced 8 AEs that led to withdrawal from treatment: 1 (Grade 3 AE of cataracts) was considered remotely related to study treatment, 4 (Grade 4 AE of thrombocytopenia/Grade 3 SAE of febrile neutropenia, Grade 2 AE of neutropenia, Grade 3 SAE of febrile neutropenia) were considered possibly related to study treatment, and 3 (Grade 4 SAE of neutropenia, Grade 4 SAE of thrombocytopenia/Grade 4 SAE of neutrophil count decreased) were considered probably related to study treatment.

RG7388 is representative of an entirely new branch of the nutlin family of MDM2 antagonists and the second agent with this mechanism of action sponsored by Roche. As with the lead compound (RO5045337), RG7388 binds selectively to the p53 site on the surface of the MDM2 molecule in vitro with high affinity and can effectively displace p53 from MDM2, leading to stabilization and accumulation of p53 protein and activation of the p53 pathway. RG7388 is from a different chemical series compared to the lead compound and binds with higher potency and selectivity to the MDM2 protein. This follow-on compound has substantially improved pharmacological properties. Preclinical models predict superior efficacy of RG7388 in the clinic at lower doses and exposures. Compared to the lead molecule, lower variability may be seen given that RG7388 does not have significant pH dependent solubility (fasted and fed-state simulated intestinal fluid solubilities are similar). RG7388 at 0.3 μM has equivalent apoptotic activity to RO5045337 at 10-fold higher (3 μM) concentration and at 25 mg/kg has equivalent efficacy to RO5045337 at 4-fold higher dose (100 mg/kg) and better potency when given once weekly.

RG7388 exhibits improved in vitro and in vivo potency against tumor cell lines and xenografts, improved CYP inhibition profile, and 2.5- to 20-fold lower projected human efficacious dose. Preclinical studies have indicated that tumors expressing wild-type p53 may respond to this novel therapeutic strategy that releases p53 from MDM2 inhibition, and tumors with wild-type p53 and MDM2 over-expression or amplification are likely to be the most sensitive. Results from preclinical safety and toxicology studies support further exploration of this compound in cancer patients. In view of the existing unmet medical need in advanced cancers expressing the above molecular signature, RG7388 is believed to be a promising agent that may offer a new therapeutic option.

The use of Pegasys in combination with other targeted agents for the treatment of PV/ET would allow for the administration of lower doses of Pegasys, thereby reducing dose dependent toxicities. Preclinical studies by Lu et al. have demonstrated preferential inhibition of PV CD34+ cell proliferation and colony formation at subtherapeutic doses of Pegasys in combination with Nutlin-3 \[33\]. Pegasys increases p53 expression through enhanced transcriptional activity via the p38 Map kinase pathway and Nutlin-3 prevents p53 degradation via interruption of the MDM2-p53 interaction \[34\]. Due to the common downstream target effect of increased tumor suppressor p53 expression with combination Pegasys and Nutlin-3, lower doses of each agent can be used together in PV patients. Thus, the use of RG7388 alone or in combination with Pegasys would be anticipated to enhance p53 expression by different mechanisms and presents a novel approach to the treatment of PV/ET.

Open Label Study of Single Agent Oral RG7388 in Patients With Polycythemia Vera and Essential Thrombocythemia

Open Label Phase I Study of Single Agent Oral RG7388 in Patients With Polycythemia Vera and Essential Thrombocythemia (With Pilot Feasibility Study in Combination With Pegylated Interferon Alfa 2a for Patients Who do Not Respond to the Single Agent at Each Dose Level)

Roche Pharma AG

The Leukemia and Lymphoma Society

John Mascarenhas

Associate Professor

Immune System Diseases

Infections

Respiratory Tract (Lung and Bronchial) Diseases

Leukemia, Lymphoid

Influenza, Human

Leukemia, Lymphocytic, Chronic, B-Cell

Communicable Diseases

Respiratory Tract Infections

Orthomyxoviridae Infections

Virus Diseases

RNA Virus Infections

Respiratory Tract Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Leukemia, B-Cell

Chronic Lymphocytic Leukemia

Vaccines

TIV (Influenza Vaccine Trivalent Inactivated) alone

15 μg (0.5 ml) through needle into arm muscle on Days 1 and 28.

Influenza Vaccine Trivalent Inactivated (TIV)

180 μg (0.5 ml) before receiving TIV, through a needle under the skin.

Pegylated interferon (PEGrIFN-α, Pegasys)

3 million units (0.5 ml) before receiving TIV, through a needle under the skin.

Interferon (IFNα, Roferon-A)

Amar Safdar, MD

The goal of this clinical study is to learn if Pegasys (pegylated interferon) or Roferon (interferon) can make the Trivalent Inactivated Influenza vaccine (TIV) more effective in increasing the body's immune reaction against the flu virus in patients with Chronic Lymphocytic Leukemia (CLL).

The Study Drugs:

Pegylated interferon and interferon are designed to stop the growth of viruses. Pegylated interferon has a molecule that makes it last longer in the body. Standard interferon does not have this molecule that makes it last longer.

TIV is designed to prevent the flu.

Screening Test:

Before you can start treatment on this study, you will have a "screening test" to help the doctor decide if you are eligible to take part in this study. Blood (about 4 teaspoons) will be drawn for routine tests. If you have had a routine blood test in the last 4 weeks, this blood will not need to be drawn. Women who are able to have children must have a negative blood (about 1 teaspoon) blood test within 2 weeks of study entry.

Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the roll of dice) to 1 of 3 groups.

If you are assigned to Group 1, you will receive TIV alone. If you are assigned to Group 2, you will receive pegylated interferon with TIV. If you are assigned to Group 3, you will receive interferon with TIV.

You will have an equal chance of being assigned to any of the 3 groups. Your doctor, the study doctor, study staff, and you will know which group you are in.

Study Drug Administration:

You will receive TIV through a needle into a muscle in your arm (the arm you do not write with) on Days 1 and 28.

* If you are in Group 1, you will only receive TIV
* If you are in Group 2, you will receive pegylated interferon right before you receive TIV. It will be given through a needle under the skin. It will be given near the TIV injection site.
* If you are in Group 3, you will receive interferon right before you receive TIV. It will be given through a needle under the skin. It will be given near the TIV injection site.

After you are given the injection(s), you will be watched for 15 minutes in the clinic before you are allowed to go home.

You will keep a diary for 1 week (7 days) after the injection(s). In it, you will record any symptoms you may be experiencing, and you will also record your body temperature.

Study Visits:

On Day 1, blood (about 4 teaspoons) will be drawn to check your immune system's response to the flu virus.

On Day 8, you will be asked to return to the clinic and your symptom/temperature diary will be reviewed. If you cannot come to the clinic, a member of the research staff will call you to review this information. This phone call will take 15-30 minutes.

On Day 28, blood (about 4 teaspoons) will be drawn to check your immune system response to the flu virus.

On Day 56, blood (about 4 teaspoons) will be drawn to check you immune system response to the flu virus. If you live out of town and cannot return to M. D. Anderson for this visit, you may have your blood drawn at a local clinic. You will then mail the blood to the study doctor in a pre-paid envelope.

On Month 6, you will be called and asked about any side effects you may have experienced. This phone call will take 15-30 minutes.

Length of Study:

You will be considered off study after the Month 6 phone call. You will be taken off-study early if intolerable side effects or an allergic reaction occurs.

This is an investigational study. TIV, pegylated interferon, and interferon are FDA approved and commercially available. At this time, the use of pegylated interferon and standard interferon with TIV is only being used for research.

Up to 60 patients will take part in this study. All will be enrolled at M. D. Anderson.

Reactogenicity, Immunogenicity of Trivalent Influenza Vaccine With Recombinant Interferon Alpha Among Chronic Lymphocytic Leukemia

A Randomized, Phase I/II Clinical Trial Evaluating the Safety, Reactogenicity, and Immunogenicity of Licensed Trivalent Influenza Vaccine Administered With Recombinant Interferon Alpha Among Patients With Chronic Lymphocytic Leukemia

Antipyretics

Anti-Inflammatory Agents

Antirheumatic Agents

Fibrinolytic Agents

Analgesics

Platelet Aggregation Inhibitors

Antisickling Agents

Aspirin

Hydroxyurea

Anti-Inflammatory Agents, Non-Steroidal

Analgesics, Non-Narcotic

Cyclooxygenase Inhibitors

Enzyme Inhibitors

The subject will begin receiving the PEGASYS at a dose level of 45 micrograms weekly and gradually get increased to the maximum dose of 180 micrograms per week. The dose will be administered by prefilled syringes that will be injected subcutaneously. Subjects will receive therapy for up to 12 months.

Subjects will receive a 500mg tablet to be taken twice daily for up to 12 months of treatment.

PEGASYS

Subject will be asked to take 81 to 100mg per day for the 12 months of the study treatment.

Claire Harrison, MD

Ruben Mesa, MD

Jean-Jacques Kiladjian, MD

Mary Frances McMullin, MD

This research is looking at two conditions, Essential Thrombocythemia (ET) and Polycythemia Vera (PV). ET causes people to produce too many blood cells called platelets and PV causes too many platelets and red blood cells to be made. Platelets are particles which circulate in the blood stream and normally prevent bleeding and bruising. Having too many platelets in the blood increases the risk of developing blood clots, which can result in life threatening events like heart attacks and strokes. When the number of red blood cells is increased in PV this will slow the speed of blood flow in the body and increases the risk of developing blood clots.

The purpose of this study is to look at the effectiveness of giving participants who have been diagnosed with ET or PV one of two different study regimens over time. The study subject will be followed for their condition for about 5 years. The subject will be randomized into one of two study regimens, either Pegylated Interferon Alfa-2a (PEGASYS) or Aspirin and Hydroxyurea (also called Hydroxycarbamide). The subject must be newly diagnosed or already receiving treatment for either PV or ET. Each of the study drugs used in this study is already being used to treat subjects with ET or PV currently, but the investigators are unsure which study drug is better.

The Philadelphia chromosome negative myeloproliferative neoplasms (MPN) are a group of clonal hematological malignancies that are characterized by a chronic course which can be punctuated by a number of disease related events including thrombosis, hemorrhage, pruritis and leukemic transformation. These disorders include Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PM). Recently an acquired somatic mutation in the intracellular kinase, JAK2 (JAK2V617F) has been observed in 95% of patients with PV, 50% of patients with ET and 50% of patients with primary myelofibrosis. At present the chemotherapeutic agent hydroxyurea is the standard of care for high risk patients with PV. Concern exists about prolonged use of this drug leading to leukemia and the inability of hydroxyurea to eliminate the malignant clone.

Interferon (rIFN -2b), is a drug that appears to be non-leukemogenic, and may have a preferential activity on the malignant clone in PV, as suggested by cytogenetic remissions obtained in patients treated with rIFN -2b. Several investigators recently reported that patients with PV treated with rIFN -2b had lower JAK2V617F allele burdens as compared to a control group that included patients treated with phlebotomy, hydroxyurea, or anagrelide, or who remained untreated. The results confirm the hypothesis that rIFN -2b preferentially targets the malignant clone in PV and raises the possibility that the JAK2V617F allele burden, and a reversion of clonal hematopoiesis monitored in females by expression of X-chromosome polymorphic alleles maybe useful in monitoring minimal residual disease in PV patients.

Pegylated Interferon Alfa-2a (PEGASYS) has been demonstrated in phase II trials of patients with PV and ET to have clinical efficacy as measured by normalization of myeloproliferation, lack of vascular events while on therapy, and a decrease in the JAK2V617F allele burden. Overall the tolerability of the therapy was good, with each of these trials having a dropout rate secondary to toxicity of less than 10% of those enrolled. Although dropout rates for toxicity were low, that is not to say the therapy was without symptomatic toxicity, and indeed a spectrum of toxicities might be encountered and need to be weighed in the analysis of the net clinical benefit patients experience on a clinical trial with Pegylated Interferon Alfa-2a.

A new MPN assessment form will be utilized in this study. This 19 item instrument includes a previously validated 9 item brief fatigue inventory (BFI), symptoms related to splenomegaly, inactivity, cough, night sweats, pruritus, bone pains, fevers, weight loss, and an overall quality of life assessment. The instrument yields an independent result for each symptom (fatigue is a composite score), as this methodology (of linear analog scale assessment \[LASA\]) has proven very valid in the past. This instrument was validated prospectively (by comparison to a panel of instruments each containing an aspect of the MPN-SAF) for administration at a single time point.

This is a randomized trial between hydroxyurea and Pegylated Interferon Alfa-2a, it is an open label clinical trial in two independent disease strata: (1) high risk polycythemia vera and (2) high risk essential thrombocythemia.

Randomized Trial of Pegylated Interferon Alfa-2a Versus Hydroxyurea in Polycythemia Vera (PV) and Essential Thrombocythemia (ET)

Randomized Trial of Pegylated Interferon Alfa-2a Versus Hydroxyurea Therapy in the Treatment of High Risk Polycythemia Vera (PV) and High Risk Essential Thrombocythemia (ET)

Number of participants with Complete Remission after 12 months of therapy assessed by hematologic response rates two strata of patients with high risk polycythemia vera (PV) or high risk essential thrombocythemia (ET). Complete remission means no evidence of disease.

Number of participants with Partial Remission after 12 months of therapy assessed by hematologic response rates two strata of patients with high risk polycythemia vera (PV) or high risk essential thrombocythemia (ET). Partial Remission means decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment.

Number of Participants with Grade 3 and Grade 4 Hematological and Non-hematological Events using the Common Terminology Criteria for Adverse Events (CTCAE) 4.0 to assess the toxicity, safety and tolerability of therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea).

Change in the Total Symptom Score which assessed improvement in disease symptoms measured by the change in TSS from the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) instrument being used in this study from baseline to 12 months. This 19 item instrument includes the previously validated 9 item brief fatigue inventory (BFI), symptoms related to splenomegaly, inactivity, cough, night sweats, pruritus, bone pains, fevers, weight loss, and an overall quality of life assessment. Each item is scored from 0-10 with full scale from 0-190, with higher scores mean worse symptoms.

To compare the impact of therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea) on key biomarkers of the disease(s) by measuring the JAK2 allele burden.

The impact of PEGASYS on JAK2 will be measured by the allele burden; hematopoietic cell clonality will be measured by whether patients with clonal disease return to polyclonal; bone marrow histopathology will be measured by going from abnormal to normal; cytogenetic abnormalities will be measured by seeing if the cytogenetics go from abnormal to normal.To compare the impact of therapy on JAK2-V617F (JAK2), CALR, hematopoietic cell clonality in platelets and granulocytes in females, bone marrow histopathology, and cytogenetic abnormalities.

Survival and incidence of development of myelodysplastic syndrome, myelofibrosis, or leukemic transformation after therapy

To estimate survival and incidence of development of myelodysplastic syndrome, myelofibrosis, or leukemic transformation after therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea) by capturing the rate of progression to a more advanced myeloid malignancy.

Myeloproliferative Disorders-Research Consortium

National Cancer Institute (NCI)

Ronald Hoffman

Professor of Medicine, Hematology and Medical Oncology

The subject received the PEGASYS at a dose level of 45 micrograms weekly and gradually increased to the maximum dose of 180 micrograms per week. The dose was administered by prefilled syringes and injected subcutaneously. Subjects received therapy for up to 12 months.

Aspirin: Subject asked to take 81 to 100mg per day for the 12 months of the study treatment.

Subjects received a 500mg tablet to be taken twice daily for up to 12 months of treatment.

Aspirin: Subject asked to take 81 to 100mg per day for the 12 months of the study treatment.

Total

Age, Continuous

Race (NIH/OMB)

Age > 60 years

The ECOG measures level of functioning in terms of daily living abilities:

0-Fully active, able to carry on all pre-disease performance without restriction

1. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, eg.light house work
2. Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about \>50% of waking hours
3. Capable of only limited selfcare; confined to bed or chair \>50% of waking hours
4. Completely disabled; cannot carry on any selfcare; totally confined to bed or chair
5. Dead

The Eastern Cooperative Oncology Group (ECOG) Performance Status

Essential thrombocythemia (ET)

Polycythemia Vera (PV)

Disease Type

Previous Thrombosis

Previous Hemorrhage

Splenomegaly

Disease Duration

Dr. Ronald Hoffman

there were 82 participants in PEGASYS arm 39 with ET and 43 with PV, 86 in Hydroxyurea arm 42 with ET and 44 with PV

Number of Participants With Complete Remission (CR)

Number of Participants With Partial Remission (PR)

Grade 3 Hematological event

Grade 4 Hematological event

Grade 3 Non-hematological event

Grade 4 Non-hematological event

Number of Participants With Grade 3 and Grade 4 Hematological and Non-hematological Events

Change in the Total Symptom Score (TSS)

JAK2 Allele Burden

Allele Burden

Death

Progression to MF

Number of Participants With Progression of Disease or Death

Number of Participants With Major Cardiovascular Events After Therapy

Thrombosis

Venous Thrombosis

Patient will start at 45 micrograms per week and gradually increase to 180 micrograms per week. Pegasys will be supplied in prefilled syringes and are to be given subcutaneously.

Ellen Ritchie, MD

Alessandro Rambaldi, MD

The aim of this research is to look at two conditions, Essential Thrombocythemia (ET) and Polycythemia Vera (PV). ET causes people to produce too many blood cells called platelets and PV causes too many platelets and red blood cells to be made. Platelets are particles which circulate in the blood stream and normally prevent bleeding and bruising. Having too many platelets in the blood increases the risk of developing blood clots, which can result in life threatening events like heart attacks and strokes. When the number of red blood cells is increased in PV this will slow the speed of blood flow in the body and increases the risk of developing blood clots.

It is important for patients with ET or PV who are at risk of blood clots to receive drugs which will minimize the risks of developing these blood clots but at the moment the investigators are not sure which drugs will best control the disorder.

The purpose of this study is to look at the effectiveness of giving patients who have been diagnosed with ET and PV a study drug regimen using Aspirin and PEGASYS (also known as Pegylated interferon alfa-2a, instead of the standard treatment drug called Hydroxyurea (or hydroxycarbamide or Hydroxyurea), for whom this drug may not be suitable. The drug may not be suitable either because it is not adequately controlling the number of blood cells or some specific side effects occur.

Myeloproliferative disorders (MPDs) are clonal hematologic diseases characterized by the excess production of one or more lineages of mature blood cells, a predisposition to bleeding and thrombotic complications, extramedullary hematopoiesis, and a variable progression to acute leukemia. The classical Philadelphia chromosome-negative MPDs are polycythemia vera (PV), characterized by an expansion in red blood cell production; essential thrombocythemia (ET), characterized by an isolated elevation in the platelet count; and myelofibrosis, distinguished by a fibrotic bone marrow and peripheral blood cytopenias, and accompanied by the highest risk of leukemic transformation. Myelofibrosis can arise de novo, as primary myelofibrosis (PMF), or can evolve out of PV or ET as those diseases progress (so called post-PV MF and post-ET MF). Amongst the MPDs, those characterized by myelofibrosis (PMF together with post-PV and post-ET MF) carry the worst prognosis, with a median survival on the order of 3 to 5 years. Patients typically present with anemia, often requiring transfusions, symptomatic splenomegaly and severe constitutional symptoms. Donor stem cell transplantation is the only potentially curative therapy. To date there is no therapy for myelofibrosis that has been shown to offer a survival benefit, and all other therapies for myelofibrosis are palliative.

In 2005, a major breakthrough in understanding the pathophysiology of MPDs came when 4 groups described a recurrent somatic mutation in Janus kinase 2 (JAK2) in the majority of patients with MPDs. The point mutation in JAK2 encodes a valine to phenylalanine change at position 617 (JAK2 V617F), and confers constitutive tyrosine kinase activity. Introducing the mutation into the bone marrow of mouse models recapitulates the PV phenotype (complete with evolution to bone marrow fibrosis) and inhibitors of JAK2 attenuate the growth of cell lines bearing the mutation in vitro and in vivo, suggesting that JAK2 V617F is a pathophysiologically relevant therapeutic target. It is estimated that 95% of PV cases carry JAK2 V617F, while 50 to 60% of ET and PMF cases are JAK2 V617F+. The discovery of the JAK2V617F mutation in nearly all patients with PV and half those with ET and PMF have redefined the classification and possibly the management of MPNs.

Despite the discovery of the JAK2V617F mutation, many of the clinical questions in the management of MPNs remain unanswered. In PV, for example, cardiovascular mortality remains 1.4 to 1.6 times that of the reference normal population with leukemia and myelofibrosis rates many times increased over baseline. Debate continues over the role of venesection versus cytoreduction as first-line therapy, and whether hydroxycarbamide (Hydroxyurea) is associated with better thrombotic prophylaxis and/or a higher rate of leukemic transformation. Interferons may produce molecular responses in PV patients. In high-risk ET, while Hydroxyurea and aspirin appear to be more optimal than anagrelide and aspirin, vascular complications remain the most significant cause of mortality and morbidity, suggesting that targeting vascular risk factors may be worthwhile.

Furthermore while Hydroxyurea is regarded as the first-choice therapy in most of high risk patients with ET and PV; up to 10% of the patients do not attain the desired reduction of platelet number or hematocrit with the recommended dose of the drug, exhibiting clinical resistance, whereas some will develop unacceptable side effects, demonstrating clinical intolerance.

Quantitation of the JAK2V617F allele burden provides for the first time the opportunity to monitor the effect of potential therapeutic agents on the malignant clone in patients with PV. Great enthusiasm has been expressed for the use of small molecule inhibitors of JAK2 for the treatment of patients with MPN. Phase 1/2 trials have indicated greater than expected toxicity, non specificity of action and an inability of these compounds to dramatically alter the JAK2V617F allele burden. Interferon (rIFN -2b), is a drug that appears to be non-leukemogenic (contrary to 32P, alkylating agents, and possibly Hydroxyurea), and may have a preferential activity on the malignant clone in PV, as suggested by cytogenetic remissions obtained in patients treated with rIFN -2b.

This trial was designed as open-label phase 2 study conducted in two strata of patients with high risk PV or ET who were intolerant of hydroxyurea. Patients with ET or PV with Splanchnic Vein Thrombosis (regardless of prior hydroxyurea) are enrolled in separate strata.

Pegylated Interferon Alfa-2a Salvage Therapy in High Risk Polycythemia Vera (PV) or Essential Thrombocythemia (ET)

Single Arm Salvage Therapy With Pegylated Interferon Alfa-2a for Patients With High Risk Polycythemia Vera or High Risk Essential Thrombocythemia Who Are Either Hydroxyurea Resistant or Intolerant or Have Had Abdominal Vein Thrombosis

Improvement in disease symptoms will be measured by the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) instrument being used in this study.

We plan to capture the rate of disease progression to a more advanced myeloid malignancy.

Capture and record the cardiovascular events that occur during the study.

The impact of PEGASYS on JAK2 will be measured by the allele burden; hematopoietic cell clonality will be measured by whether patients with clonal disease return to polyclonal; bone marrow histopathology will be measured by going from abnormal to normal; cytogenetic abnormalities will be measured by seeing if the cytogenetics go from abnormal to normal.

Digestive System Diseases

Colonic Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Two 45 mikrogram doses of interferon-alfa2a (Pegasys). Both will be applied subcutanously. First dose is at least one week before surgery. Second dose on the day of surgery before the procedure.

Two 1 ml doses of saline liquid. Both will be applied subcutanously. First dose is at least one week before surgery. Second dose on the day of surgery before the procedure.

45 mikrograms of Pegasys. Two subcutanous doses will be administered with at least 7 days in between

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pegasys in Patients With Chronic Myeloid Leukemia (CML)	NCT01392170	Leukemia	PEG-IFNá-2a	16 Years -	M.D. Anderson Cancer Center
Open Label Study of Single Agent Oral RG7388 in Patients With Polycythemia Vera and Essential Thrombocythemia	NCT02407080	Polycythemia Ve... Essential Throm...	RG7388 Pegasys	18 Years -	Icahn School of Medicine at Mount Sinai
Pegasys in Patients With Chronic Myeloid Leukemia (CML)	NCT01392170	Leukemia	PEG-IFNá-2a	16 Years -	M.D. Anderson Cancer Center
Reactogenicity, Immunogenicity of Trivalent Influenza Vaccine With Recombinant Interferon Alpha Among Chronic Lymphocytic Leukemia	NCT00962715	Chronic Lymphoc...	Influenza Vacci... Pegylated inter... Interferon (IFN...	18 Years -	M.D. Anderson Cancer Center
Randomized Trial of Pegylated Interferon Alfa-2a Versus Hydroxyurea in Polycythemia Vera (PV) and Essential Thrombocythemia (ET)	NCT01259856	High Risk Polyc... High Risk Essen...	PEGASYS Hydroxyurea Aspirin	18 Years -	Icahn School of Medicine at Mount Sinai
Pegylated Interferon Alfa-2a Salvage Therapy in High Risk Polycythemia Vera (PV) or Essential Thrombocythemia (ET)	NCT01259817	High Risk Polyc... High Risk Essen...	PEGASYS Aspirin	18 Years -	Icahn School of Medicine at Mount Sinai
Open Label Study of Single Agent Oral RG7388 in Patients With Polycythemia Vera and Essential Thrombocythemia	NCT02407080	Polycythemia Ve... Essential Throm...	RG7388 Pegasys	18 Years -	Icahn School of Medicine at Mount Sinai
Effect of Low-dose Interferon-alfa2a on Peri-operative Immune Suppression	NCT04798612	Colon Cancer	Pegasys Saline	18 Years -	Zealand University Hospital
Pegasys in Patients With Chronic Myeloid Leukemia (CML)	NCT01392170	Leukemia	PEG-IFNá-2a	16 Years -	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for pegasys

Every month we try and update this database with for pegasys cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for pegasys

Every month we try and update this database with for pegasys cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for pegasys cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.