Oral cytobrushing

This study will examine the effects of certain investigational anti-cancer drugs on the genetic and protein makeup of cells. The findings will be entered into a database that may be used to: 1) determine the optimal dose of drug that will provide the most benefit with the least harmful side effects; and 2) predict which patients will have a greater chance of developing side effects or a greater chance of benefiting from the drug.

Patients 18 years of age and older who are receiving the anti-cancer drugs flavopiridol or perifosine in an NIH clinical trial may be eligible for this study.

Participants will undergo the following procedures both before starting treatment and during the first treatment cycle to look for genetic or chemical changes produced in response to the study drug:

* Blood draws.
* Buccal cell brushings: Collection of buccal cells (cells lining the inside of the cheeks) from the inside of the cheeks using a soft bristle brush for a few seconds several times. The patient then rinses the mouth with salt water for 1 minute and then spits into a cup.
* Buccal cell biopsies (on both sides of the mouth): For this procedure, a local anesthetic is given to numb the biopsy area. Then, a small piece of tissue from the inner lining of the mouth is removed with a small sharp cookie-cutter instrument. The biopsy findings will be compared with those of the cheek brushings to see if the information is similar.
* Tumor biopsies: In patients whose tumor is easily accessible, such as the skin abdominal fluid, tissue biopsies will be requested. Depending on the type and location of the tumor, the biopsy may be done with a forceps, a large needle (needle biopsy), a cookie-cutter instrument (punch biopsy), or a small knife (excisional biopsy). All of these procedures are done with a local anesthetic.

A significant problem in drug development of novel small molecules is the lack of available tissues (surrogate tissues) that allow for the assessment of the molecular and biochemical effects of (targeted-therapies) drug action. The information obtained from surrogate tissues might help us validate previous preclinical studies with those agents and also dose them in a more rational way. Oral keratinocytes, which are accessible by non-invasive means, might be useful to assess drug action. The proposed study seeks to investigate the genetic, molecular, and biochemical effects of novel agents in oral buccal mucosal cells. Patients already enrolled in Phase I and II clinical trials for neoplastic diseases at the Clinical Center will undergo oral cytobrushing before and during therapy to determine the molecular and biochemical effects of novel agents in the oral mucosa cells. Similar studies will be performed in peripheral blood mononuclear cells. In order to validate to compare and compare the oral cytobrush methodology, some of these subjects will undergo oral punch biopsy studies. Some of these subjects will also undergo tumor biopsy, if accessible or available.

Chemical and Genetic Effects of the Experimental Anti-Cancer Drugs in Cheek Cells in Cancer Patients

Molecular, Genetic, and Biochemical Effects Of Novel Therapies In Buccal Mucosal Cells

National Institute of Dental and Craniofacial Research (NIDCR)

Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Syndrome

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Leukemia, Lymphocytic, Chronic, B-Cell

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Preleukemia

Myelodysplastic Syndromes

Lymphoma

Neoplasms by Histologic Type

Hematologic Diseases

Bone Marrow Diseases

Precancerous Conditions

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Leukemia, B-Cell

Chronic Disease

Disease Attributes

Myeloproliferative Disorders

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Chronic Graft Versus Host Disease

Acute Non Lymphoblastic Leukemia

Chronic Lymphocytic Leukemia

Chronic Myeloid Leukemia

Acute Graft Versus Host Disease

Lymphosarcoma

Chronic Myeloproliferative Disorders

Pharmaceutical Solutions

All Drugs and Chemicals

Antineoplastic Agents

ON 01910

Protein Kinase Inhibitors

Enzyme Inhibitors

The starting dose is 650 mg/m2 per day for 3 continuous days every 2 weeks. In successive courses, infusion time may be increased by 1 day up to 7 days every two weeks and/or drug dose may be increased (650, 1050, 1700 mg/m2/day, etc.). After 4 2-week cycles, cycle length may be extended to 3 or 4 weeks. Treatment continues until evidence of disease progression, intolerable adverse events or withdraw of consent.

The drug is a sterile, concentrated 75mg/mL solution in polyethylene glycol 400, in labeled, sealed glass vials. The Concentrate must be diluted with aqueous infusion solutions (0.9% NaCl, USP and Water for Injection, USP according to instructions) immediately prior to intravenous administration.

ON 01910.Na

Lewis R. Silverman, MD

This is an open-label, Phase I study to determine the highest amount of the study drug, ON 01910.Na, that can be safety given to patients with high risk myelodysplastic syndromes (MDS) or refractory leukemias. Patients will receive ON 01910.Na (at a starting dose of 650 mg/m2) intravenously by 3-day continuous infusion once every 2 weeks. Successive courses will use longer infusion times and/or higher doses of the drug until toxicity, effectiveness, or ineffectiveness is recognized. In addition, the amount of drug in the blood will be measured, any antitumor activity will be documented, and the biological effect of ON 01910.Na on cell-cycle pathways will be evaluated in peripheral blood mononuclear cells.

Patients must have histologically documented or cytologically confirmed diagnosis of acute myelocytic leukemia refractory to standard induction treatment, or relapsed after standard therapy; acute lymphocytic leukemia refractory to induction treatment, or relapsed after effective therapy; chronic myelocytic leukemia refractory to imatinib therapy or second line tyrosine kinase inhibition, or relapsed after tyrosine kinase inhibition, in chronic, accelerated, or blastic phase; chronic lymphocytic leukemia refractory to standard therapy, or relapsed in second relapse; a myelodysplastic syndrome (including chronic myelomonocytic leukemia) refractory to azacitidine; and an int-2 or high myelodysplastic syndrome relapsed after a hypomethylating agent. Patients may not be eligible for, or must have declined, bone marrow transplantation or other chemotherapeutic regimens known to produce consistent remissions. Because hematopoietic criteria in leukemia and lymphoma are confounded by the nature of the diseases themselves, there are no hematologic exclusions from treatment. If leukopenia is clinically determined to be attributable to prior treatment, ON 01910.Na treatment may start when the leukocyte count increases on two successive determinations performed at least three days apart. Thrombocytopenia is not a criterion, and patients will be supported with platelet transfusions as clinically necessary. In the absence of leukopenia, a failed prior treatment may be succeeded immediately by entry into study of ON 01910.Na if the leukocyte count is stable or rising, on two successive determinations performed at least three days apart, in the absence of other drug toxicity.

The patient population will involve approximately 12 to 28 patients ≥ 18 years of age in the dose escalation portion of the protocol. All patients must have relapsed or refractory leukemia or poor risk MDS (i.e., int-2 or high risk MDS who have failed standard therapy). They must not be candidates for known regimens or protocol treatments of higher efficacy or priority. Patients with relapsed/refractory leukemia or poor risk MDS must have an ECOG Performance Status of 0, 1, or 2. Patients must have an expected survival, in the opinion of the Investigator, to allow a sufficient observation period for evaluating ON 01910.Na, and meet the eligibility criteria for patients with leukemia or poor risk MDS. After the maximally tolerated dose and the Recommended Phase II Dose (RPTD) and duration are determined, up to 12 additional patients with histologically documented or cytologically confirmed leukemia or poor risk MDS will be added to confirm the appropriateness of the RPTD. Inclusion criteria for the dose confirmation phase will be similar to those of the dose escalation phase of the study, but the ECOG Performance Status must be 0 or 1.

Safety data, including laboratory parameters and adverse events, will be collected for all patients in order to determine the qualitative and quantitative toxicity, and reversibility of toxicity, of ON 01910.Na. Leukemic cells and MDS cells in peripheral blood will be measured on a daily basis during infusion, and at least two times weekly during the following week. If leukemic cells disappear from the blood or blood counts improve as defined by IWG criteria in MDS patients, a bone marrow aspiration will be performed to determine response status in the bone marrow.

All patients may continue therapy for at least six cycles unless rapid disease progression is documented. Patients with an objective clinical response or stable disease can continue up to six more cycles. Further continuation will be determined by the clinical judgment of the Investigator.

Phase I Study of ON 01910.Na in Refractory Leukemia or Myelodysplastic Syndrome (MDS)

Phase I Dose Escalation Study of ON 01910.Na With Increasing Duration of an Initial 3-Day Continuous Infusion in Patients With Refractory Leukemia or MDS

Traws Pharma, Inc.

Respiratory Tract (Lung and Bronchial) Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Digestive System Diseases

Diseases and Abnormalities at or Before Birth

Nutritional and Metabolic Diseases

Carcinoma, Non-Small-Cell Lung

Prostatic Neoplasms

Carcinoma

Carcinoma, Squamous Cell

Lung Neoplasms

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Anemia

Anus Neoplasms

Fanconi Syndrome

Fanconi Anemia

Lymphoma, Non-Hodgkin

Ovarian Cancer

Ovarian Epithelial Cancer

Anal Cancer

Congenital Aplastic Anemia

SRA737 will be administered orally on each day of a 28-day cycle. Subjects will receive a single dose of SRA737 between 4 to 7 days prior to starting the first cycle for PK profiling. Subjects can continue taking SRA737 if they are receiving clinical benefit and able to safely take the drug and follow the requirements of the study.

SRA737

The purpose of this clinical study is to establish the safety profile, determine the maximum tolerated dose (MTD) and recommend a Phase 2 dose and schedule of SRA737; and to evaluate the efficacy of SRA737 in prospectively-selected subjects with genetically-defined tumors that harbor genomic alterations linked to increased replication stress and that are hypothesized to be more sensitive to checkpoint kinase 1 (Chk1) inhibition via synthetic lethality. Specific cancer indications that frequently harbor these genetic mutations will be studied.

SRA737 is a potent, highly selective, orally bioavailable small molecule inhibitor of Chk1, a key regulator of cell cycle progression and the DNA Damage Response (DDR) replication stress response. In cancer cells, intrinsic replication stress (RS) is induced by factors such as oncogenes (e.g., CCNE1 or MYC), genetic mutations in DNA repair machinery (e.g. BRCA1 or FANCA), genetic mutations leading to a dysregulated cell cycle (e.g., TP53 or RAD50) or other genomic alterations. This replication stress results in persistent DNA damage and genomic instability, leading to an increased dependency on Chk1 for survival. Targeted inhibition of Chk1 by SRA737 may therefore be synthetically lethal to cancer cells with elevated intrinsic RS.

This study has been designed to: establish the safety profile; determine the pharmacokinetic profile; identify the optimal dose, schedule, and MTD; obtain preliminary evidence of activity; and evaluate SRA737's efficacy in prospectively-selected subjects with tumors that harbor genomic alterations linked to increased replication stress and that are hypothesized to be more sensitive to Chk1 inhibition via synthetic lethality.

This clinical study consists of two phases, a Dose Escalation Phase 1 portion and a Cohort Expansion Phase 2 portion.

In the Dose Escalation Phase 1 portion, cohorts consisting initially of a single subject will receive escalating doses of SRA737, administered orally on a continuous daily dosing schedule in 28-day cycles. Once an SRA737-related Grade 2 toxicity is observed in a dose escalation cohort during Cycle 1, that cohort will be expanded to 3 to 6 subjects, and subsequent dose level cohorts will follow a rolling 6 design until the MTD has been identified.

In the Cohort Expansion Phase 2 portion, subjects with genetically-defined tumors that harbor genomic alterations linked to increased replication stress and that are hypothesized to be more sensitive to Chk1 inhibition will be prospectively enrolled into six indication-specific cohorts to explore the preliminary efficacy of SRA737. Subjects must have advanced or metastatic disease of one of the following types:

* castration-resistant prostate cancer (mCRPC);
* high grade serous ovarian cancer (HGSOC) without CCNE1 gene amplification;
* HGSOC with CCNE1 gene amplification (or alternative genetic alteration with similar functional effect);
* non-small cell lung cancer (NSCLC);
* head and neck squamous cell carcinoma (HNSCC) or squamous cell carcinoma of the anus (SCCA); and
* colorectal cancer (mCRC).

To qualify for enrolment in the Cohort Expansion Phase 2 portion, the subject's tumor must have a confirmed combination of mutations which are expected to confer sensitivity to Chk1 inhibition, determined by the Sponsor's review of genetic abnormalities detected in the following categories:

* Oncogenic drivers such as CCNE1 or MYC, etc.
* Genes involved in the DNA repair process including BRCA1, BRCA2, FANC genes, mismatch repair (MMR) genetic alterations and/or high microsatellite instability.
* Key tumor suppressor genes regulating G1 cell cycle progression/arrest such as TP53, RAD50, etc. For patients with HNSCC or SCCA, positive human papilloma virus (HPV) status is also considered for eligibility.
* Genetic indicators of replicative stress such as gain of function/amplification of CHEK1, ATR or other related genes.

Tumor genetics will be prospectively determined using Next-Generation Sequencing.

A Phase 1/2 Trial of SRA737 in Subjects With Advanced Cancer

A Phase 1/2 Trial of SRA737 (a Chk1 Inhibitor) Administered Orally in Subjects With Advanced Cancer

Treatment-emergent adverse events (TEAEs) were reported until the safety Follow up (SFU) visit, 30 days after the last dose of SRA737 or prior to the initiation of a new anticancer treatment, whichever came first.

The highest dose at which ≤ 33% of subjects have a dose limiting toxicity (DLT) in a cohort of up to 6 subjects.

The RP2D and schedule were defined by the Cohort Review Committee at the end of the study and took all clinically relevant toxicity, PK and PDn data into account. The RP2D was to be a dose equal to or less than the MTD for the selected schedule.

The disease control rate (DCR) was defined as the number of subjects achieving complete response (CR) + partial response (PR) + stable disease (SD) per RECIST 1.1 criteria. Since no subjects achieved CR or PR in this study, the DCR represents the proportion of subjects in each group who achieved SD.

Time to progression (TTP) was defined as the time from Cycle 1 Day 1 to the earliest date of radiographic disease progression per RECIST 1.1, or if the subject did not experience disease progression, to the last imaging assessment. TTP was analyzed using the K-M method.

Progression free survival (PFS) was defined as time from Cycle 1 Day 1 to the earliest date of radiographic disease progression per RECIST 1.1 or death, whichever happened first. Censoring rules are defined in the SAP. PFS was analyzed using the K-M method.

Overall survival (OS) was defined as time from Cycle 1 Day 1 to the date of death (or date last known to be alive). OS was analyzed using the K-M method.

Sierra Oncology LLC - a GSK company

An AE was defined as any untoward, undesired, or unplanned medical occurrence in a subject administered SRA737. All AEs and SAEs were assessed for seriousness, causality, and expectedness.

As specified in the Statistical Analysis Plan, the frequency of each AE was evaluated in the overall Safety Evaluable Population (all enrolled subjects who receive at least 1 dose of SRA737) of patients with advanced solid tumors, irrespective of tumor type. All AEs collected are included in the summary.

Due to the small numbers of patients in some tumor type subgroups and with the intention of displaying the overall safety profile of SRA737 in advanced solid tumors, the frequency of each AE was evaluated in the overall Safety Evaluable Population rather than by tumor type subgroups. The Safety Evaluable Population includes all enrolled subjects who receive at least 1 dose of SRA737.

Safety Evaluable Population

Metastatic colorectal cancer (CRC) defined as histologically and/or cytologically confirmed CRC, and must have received at least 1 prior regimen for advanced/metastatic disease.

Colorectal Cancer

High grade serous ovarian cancer (HGSOC) defined as histologically confirmed high grade serous ovarian, fallopian tube or primary peritoneal cancer who were recurrent platinum intolerant, or with platinum resistant disease defined as radiological evidence of disease progression within 6 months of the last receipt of platinum based chemotherapy.

High Grade Serous Ovarian Cancer

Advanced non small cell lung cancer (NSCLC) defined as locally advanced and recurrent or metastatic, histologically confirmed NSCLC, and must have received at least 1 prior regimen for advanced/metastatic disease.

Non Small Cell Lung Cancer

Metastatic castration resistant prostate cancer (mCRPC) defined as histologically or cytologically confirmed adenocarcinoma of the prostate that has progressed after androgen deprivation therapy.

Metastatic Other Tumor Type Castration Resistant Prostate Cancer

Histologically confirmed HNSCC from any primary site; locally advanced disease (ie, persistent or progressive disease following curative intent radiation, and not a candidate for surgical salvage due to incurability or morbidity), or metastatic disease.

Head and Neck Squamous Cell Carcinoma

Any locally advanced or metastatic, histologically or cytologically proven solid tumor or NHL, that had relapsed after or progressing despite conventional treatment for which no conventional therapy was considered appropriate by the investigator or had been declined by the subject.

Other Tumor Type

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

American Indian or Alaska Native

Asian

Black or African American

Native Hawaiian or Other Pacific Islander

White

Other

Not Reported

Race/Ethnicity, Customized

United Kingdom

Region of Enrollment

The Safety Evaluable Population includes all enrolled subjects who receive at least 1 dose of SRA737.

GSK Response Center

As specified in the Statistical Analysis Plan, the frequency of each AE was evaluated in the overall Safety Evaluable Population rather than by tumor type subgroups with the intention of displaying the overall safety profile of SRA737 in advanced solid tumors. The Safety Evaluable Population includes all enrolled subjects who receive at least 1 dose of SRA737.

Number of Subjects With Adverse Events as Assessed by CTCAE 4.03

The Dose Escalation Phase included a total of 18 subjects in 9 different dosage cohorts: 20 mg QD, 40 mg QD, 80 mg QD, 160 mg QD, 300 mg QD, 600 mg QD, 1000 mg QD, 500 mg BID, and 1300 mg QD.

Dose Escalation Phase

In order to determine the MTD, a total of 18 subjects were enrolled in the dose escalation phase of the study in 9 dosage cohorts. All subjects receiving at least 75% of planned doses of SRA737 within Cycle 1 and those subjects receiving less than these planned doses of SRA737 due to DLT were considered evaluable for dose review decisions.

Maximum Tolerated Dose of SRA737

All 107 subjects treated in the study were included in the review of toxicity, PK and PDn, data in order to determine the RP2D. All clinically relevant toxicity, PK and PDn data up to 30 days after last dose of SRA737 were taken into account.

Recommended Phase 2 Dose of SRA737

The Response Evaluable Population (REP) included all enrolled subjects who satisfy all of the following conditions:

1. Measurable disease and assessment at baseline
2. Received at least 75% of 1 cycle of study medication, based on dosing information
3. At least one post baseline disease assessment OR discontinued treatment due to AE or disease progression or death

Disease Control Rate (DCR) of SRA737

Time to Progression (TTP)

Progression Free Survival (PFS)

Metastatic Castration Resistant Prostate Cancer

All subjects included in the Response Evaluable Population

Overall

The Response Evaluable Population (REP) included all subjects who satisfy the following conditions:

1. Measurable disease and assessment at baseline
2. Received at least 75% of 1 cycle of study medication, based on dosing information
3. At least 1 post baseline disease assessment OR discontinued treatment due to AE or disease progression or death Note: The median OS was not estimated in the mCRPC, HNSCC, or "Other" tumor type subgroups due to insufficient number of participants with events.

Overall Survival (OS)

Overall Study

Infections

Sarcoma

Acquired Immunodeficiency Syndrome

HIV Infections

Sarcoma, Kaposi

Neoplasms, Connective and Soft Tissue

Communicable Diseases

Herpesviridae Infections

Virus Diseases

DNA Virus Infections

Neoplasms, Vascular Tissue

Soft Tissue Sarcoma

Kaposi Sarcoma

Abemaciclib (at optimal dose determined in dose escalation portion of the study) for up to 15 participants previously treated with at least 1 line of systemic therapy.

Abemaciclib (at optimal dose determined in dose escalation portion of the study) for up to 10 previously untreated participants.

An initial dose of 200 mg twice daily and at an MTD dose will be administered orally every day of each 28-day cycle.

Abemaciclib

Anaida Widell

Ramya M Ramaswami, M.D.

For more information at the NIH Clinical Center contact National Cancer Institute Referral Office

Background:

Kaposi Sarcoma (KS) is common in people with human immunodeficiency virus (HIV) but can also occur in people who do not have HIV. KS tumors usually involve the skin, but may also involve lymph nodes, lungs, bone, and gastrointestinal tract. Researchers want to see if a drug that is currently used to treat a type of breast cancer can help.

Objective:

To find a safe dose of abemaciclib to treat KS and to see if it can shrink lesions or tumors.

Eligibility:

People ages 18 and older with KS.

Design:

Participants will be screened with some or all of the following:

Medical history

Physical exam

Blood and urine tests

Chest x-ray and/or computed tomography scans

Lung or gastrointestinal tract exam with an endoscope (a flexible instrument to examine the interior of the organ)

Medicine review

Heart function tests

KS lesion assessment

Skin sample from a KS lesion

Treatment will be given in 28-day cycles. Participants will take the study drug tablets by mouth everyday. They will keep a medicine diary. They will get the study drug until their cancer gets worse or they have unacceptable side effects.

Participants will have a study visit at the beginning of each cycle. At these visits, they will repeat some screening tests. They may have medical photographs taken of body surfaces. They may complete questionnaires about their quality of life. They may give skin and saliva samples. For skin samples, an area of skin will be numbed. A small circle of skin over an area affected by KS will be removed.

Participants will have follow-up visits for up to 2 years after treatment ends.

Background:

* Kaposi Sarcoma (KS) is a multicentric angioproliferative tumor, caused by Kaposi sarcoma-associated herpesvirus, that most frequently involves the skin, but may also involve lymph nodes, lungs, bone and gastrointestinal tract. It is most common in people with HIV but may also occur in patients without a diagnosis of HIV. Patients with HIV-associated KS have worse survival than HIV-infected patients without KS.
* As it is a relapsing and remitting condition, patients with KS often require prolonged courses of cytotoxic chemotherapy and improved approaches for refractory and recurrent KS are needed to decrease morbidity among patients with KS.
* Cell cycle dysregulation is one of the hallmarks of cancer and has been developed as a therapeutic target in patients with metastatic breast cancer. Cell cycle is controlled by several proteins, including cyclin D kinases (CDKs), cyclins and retinoblastoma (Rb)-E2F signaling pathway.
* Abemaciclib is an orally available cyclin-dependent kinase (CDK) inhibitor that targets the CDK4 (cyclin D1) and CDK6 (cyclin D3) cell cycle pathways thereby inhibiting retinoblastoma (Rb) protein phosphorylation in early G1.
* KS is an endothelial tumor, and KSHV-infected endothelial cells serve as the best current model for KS as there are no good animal models for this disease. Abemaciclib was found to inhibit proliferation of KSHV-infected and uninfected human umbilical vein endothelial cells (HUVEC) at doses as low as 0.1 microM.
* Published Phase I/II studies demonstrated that abemaciclib led to clinical responses in patients with metastatic breast cancer and other tumor types, such as glioblastoma, colorectal cancer, and melanoma.
* Abemaciclib is a therapy licensed for use in metastatic breast cancer both as monotherapy and in combination with other cancer therapies and the safety and efficacy profiles of this agent are very well known. We hypothesize that abemaciclib will be well-tolerated and patients with KS who have received prior therapies will derive some clinical benefit.

Objectives:

-To evaluate the safety and tolerability of abemaciclib in participants with both untreated and previously treated Kaposi sarcoma

Eligibility:

* Age \>=18 years
* Histologically confirmed Kaposi sarcoma (KS)
* KS requiring systemic therapy, with either no prior systemic therapy or history of at least 1 prior line of systemic therapy:

  * 3 weeks from last chemotherapy
  * 3 weeks from last immunotherapy
* At least five measurable cutaneous KS lesions with no previous local radiation, surgical or intralesional cytotoxic therapy to these measurable lesions.
* ECOG Performance Status (PS) \<= 2
* Participant must be willing to give informed consent.
* Participants can be HIV positive or negative.
* Antiretroviral therapy (ART) for HIV+ participants
* Participants receiving other investigational agents will not be eligible.

Design:

* This is a phase I/II study assessing the safety and efficacy of abemaciclib in participants with previously untreated or treated KS.
* In the phase I portion of the study, up to 18 KS participants treated with prior therapy will be enrolled in a 3+3 dose de-escalation schema using 2 dose de-escalation levels.
* Following identification of an optimal dose and schedule, an expansion phase (Phase II) will be initiated. Up to 25 previously untreated or treated KS participants will be enrolled.
* Abemaciclib will be administered as an oral planned starting dose of 200 mg twice daily (in the morning and evening) without regard to meals. Abemaciclib will be given continuously; one cycle equals 28 days.
* Participants will receive therapy until optimal tumor response, unacceptable toxicity, the participant s request to discontinue therapy, or PI decision. Participants with disease progression will have the option of an additional 12 weeks of treatment, if the PI feels that they are deriving clinical benefit.

Abemaciclib in Patients With HIV-associated and HIV-negative Kaposi Sarcoma

A Phase I/II Study of Abemaciclib in Patients With HIV-associated and HIV-negative Kaposi Sarcoma

.All IPD recorded in the medical record will be shared with intramural investigators upon request.

The fraction of patients with toxicity noted at each dose level will be reported by grade and type of toxicity identified.

Percentage of patients with the best overall response of CR or PR to therapy

Staging and response to abemaciclib for KS by the evaluation of number, size, nodularity, and color of lesions.

The time criteria are met for CR or PR (whichever is recorded first) until the first date that patient no longer qualifies as a PR

Duration of time from the start of the treatment until time of disease relapse from PR, disease progression, or death, whichever occurs first

National Cancer Institute (NCI)

Recurrence

Squamous Cell Carcinoma of Head and Neck

Head and Neck Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms, Squamous Cell

Anti-Infective Agents

Bortezomib

HIV Protease Inhibitors

Protease Inhibitors

Proteasome Inhibitors

bortezomib

radiation therapy

Carter Van Waes, M.D.

This study will test the safety and effects of the experimental drug PS-341 plus radiation therapy in patients with head and neck cancer. PS-341 can slow or halt the growth of cancer cells grown in culture or in mice. In addition, the drug appears to enhance the effectiveness of radiation treatment.

Patients 18 years of age and older with head and neck cancer that cannot be treated adequately with surgery and cannot be cured with standard radiation and chemotherapy may be eligible for this study. Patients whose cancer has spread to the brain may not participate.

Before treatment begins participants are evaluated with CT or MRI scans of the head, neck and chest area to determine the extent of the cancer; an electrocardiogram and blood tests; and a neurocardiovascular evaluation that includes measuring blood pressure in different body positions and involves injections of phenylephrine and nitroglycerine. Some patients may undergo a procedure in which a tube is inserted into the larynx (voice box), bronchi (breathing tubes) and esophagus (food tube) and tissue samples removed. This procedure is done under general anesthesia in the operating room.

Patients receive radiation treatments Monday through Friday and injections of PS-341 twice a week during the radiation therapy. After 3 weeks of treatment, PS-341 injections are stopped for 2 weeks. Some patients continue to receive radiation treatments during the 2-week break, and others do not, depending upon when they enter the trial. The total duration of radiation treatment varies from 6 to 8 weeks, depending on whether the patient received radiation in the region of the head and neck cancer before entering the study.

Patients have a blood sample drawn before and after each new PS-341 injection to measure the drug action in the blood and to see how strong and how long the effects on the blood last. They are seen in the clinic at least once a week for a history and physical examination. A blood sample is collected at each visit to look for toxic effects of PS-341. Near the end of treatment, the neurocardiovascular evaluation is repeated, and if the results are abnormal, it is repeated again 3 months after treatment is completed. X-rays or MRI scans are done 12 weeks after radiation therapy has ended and then every few months after that to determine the extent of disease. Patients whose tumor is accessible are asked to undergo a biopsy (removal of a small piece of tumor tissue) on the first and second day after receiving the first PS-341 dose to examine the effect of the drug on the tumor.

The PS-341 dose is increased in successive groups of at least 3 patients until the highest dose that can be given safely with radiation is reached. Patients who develop severe side effects from the drug temporarily stop taking it to allow the side effects to improve. If needed, the dose may be decreased. Radiation therapy may also be stopped temporarily in patients who develop severe effects on the mouth, throat or skin. Side effects may be treated with increased fluid (by mouth, stomach tube, or vein), anti-nausea or anti-diarrhea medications, pain medications and medications to boost red or white cell counts or platelets. The drug Florinef may be given to help regulate body fluids and blood pressure.

...

Background:

* The ubiquitin-proteasome pathway regulates the degradation of important regulatory proteins and transcription factors that control the cell cycle and cell death. Proteasome inhibition can lead to block of different phases of the cell cycle, and block expression of genes that prevent cell death induced by radiation or other cytotoxic therapeutic agents.
* In preclinical studies, proteasome inhibitor PS-341 has demonstrated cytotoxic, radiosensitizing, and anti-tumor activity against squamous cell carcinomas of the head and neck (SCCHN).

Objectives:

* The primary objective of this phase I dose escalation clinical study is to determine the maximum tolerated dose of PS-341 to be given concomitant with radiation in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.
* Secondary objectives include detection of 20S proteasome inhibition, cell cycle block, apoptosis and inhibition of transcription factor NF-kappaB activation in tumor tissue biopsies following PS-341 and radiation.

Eligibility:

* Persistent or recurrent SCCHN,
* Eligible for local primary or re-irradiation,
* ECOG performance less than or equal to 2, life expectancy \> 3 months,
* Adequate organ function (PLT \> 100, 000/microL, neutrophils \> 1500/mciroL, serum creatinine \< 1.5 times the upper limits normal (ULN), serum bilirubin \< 1.5 times the ULN, serum transaminases \< 2.5 times the ULN)
* No systemic chemotherapy within the past 4 weeks and recovered from chemotherapy toxicity,
* \> 6 months since prior radiation.

Design:

* Phase I dose escalation, standard 3+3 statistical design, up to 51 subjects,
* PS-341 will be given in escalating doses of 0.6, 0.9 and 1.2 mg/m(2) in cohorts of 3 or more patients by IV bolus on M, Th (or T, F), and radiation will be given in 1.8 Gy fractions M-F to 60 Gy in previously radiated or 72Gy in previously unirradiated patients.
* Radiation and/or drug will be given in two courses split by a two week rest to allow recovery from combined modality therapy.

PS-341 and Radiation to Treat Advanced Cancer of the Head and Neck

A Phase I Study of Concomitant Therapy With Proteasome Inhibitor PS-341 and Radiation in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Chemical and Genetic Effects of the Experimental Anti-Cancer Drugs in Cheek Cells in Cancer Patients	NCT00055380	Cancer	Oral cytobrushi...	-	National Institutes of Health Clinical Center (CC)
Phase I Study of ON 01910.Na in Refractory Leukemia or Myelodysplastic Syndrome (MDS)	NCT00854646	Acute Myelocyti... Acute Lymphocyt... Chronic Myelocy... Chronic Lymphoc... Myelodysplastic...	ON 01910.Na	18 Years -	Traws Pharma, Inc.
Phase I Study of ON 01910.Na in Refractory Leukemia or Myelodysplastic Syndrome (MDS)	NCT00854646	Acute Myelocyti... Acute Lymphocyt... Chronic Myelocy... Chronic Lymphoc... Myelodysplastic...	ON 01910.Na	18 Years -	Traws Pharma, Inc.
A Phase 1/2 Trial of SRA737 in Subjects With Advanced Cancer	NCT02797964	Advanced Solid ...	SRA737	18 Years -	Sierra Oncology LLC - a GSK company
Abemaciclib in Patients With HIV-associated and HIV-negative Kaposi Sarcoma	NCT04941274	Kaposi Sarcoma	Abemaciclib	18 Years -	National Institutes of Health Clinical Center (CC)
Chemical and Genetic Effects of the Experimental Anti-Cancer Drugs in Cheek Cells in Cancer Patients	NCT00055380	Cancer	Oral cytobrushi...	-	National Institutes of Health Clinical Center (CC)
PS-341 and Radiation to Treat Advanced Cancer of the Head and Neck	NCT00011778	Squamous Cell C...	bortezomib radiation thera...	18 Years -	National Institutes of Health Clinical Center (CC)
Phase I Study of ON 01910.Na in Refractory Leukemia or Myelodysplastic Syndrome (MDS)	NCT00854646	Acute Myelocyti... Acute Lymphocyt... Chronic Myelocy... Chronic Lymphoc... Myelodysplastic...	ON 01910.Na	18 Years -	Traws Pharma, Inc.
A Phase 1/2 Trial of SRA737 in Subjects With Advanced Cancer	NCT02797964	Advanced Solid ...	SRA737	18 Years -	Sierra Oncology LLC - a GSK company
Abemaciclib in Patients With HIV-associated and HIV-negative Kaposi Sarcoma	NCT04941274	Kaposi Sarcoma	Abemaciclib	18 Years -	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for cell cycle

Every month we try and update this database with for cell cycle 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 cell cycle

Every month we try and update this database with for cell cycle 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 cell cycle 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.