Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Treatment with 4.8 grams PectaSol-C Modified Citrus Pectin three times a day, away from meals for six months.

Oral administration of PectaSol-C MCP (4.8 grams in six capsules three times a day away from food).

PectaSol-C Modified Citrus Pectin (MCP)

Daniel Keizman, MD

Isaac Eliaz, MD, LAc, MS

Moshe Frenkel, MD

To determine if the oral administration of PectaSol-C Modified Citrus Pectin (MCP) is effective at improving Prostate Specific Antigen (PSA) kinetics in men with biochemical relapsed prostate cancer and serial increases in PSA levels. Also, documentation of any side effects or benefits within parameter of the study is included.

This study on the effect of PectaSol-C Modified Citrus Pectin (MCP) with subjects selected on the basis of documented PC post local therapy, and biochemical relapse, with linear progression of at least 3 PSA tests in at least 3 months. After initial screening, treatment {4.8 grams (6 capsules) three times a day away from meals} will continue for 6 months provided patients are showing benefit and tolerating the therapy well. Patient tolerability of MCP will be assessed by comparing the results of monthly self-assessment diaries with baseline assessments.

Prostate cancer is the most common cancer among men, except for non melanoma skin cancer. It is the second leading cause of cancer related death in men. About 33% of prostate cancer patients treated with primary therapy (surgery or radiation) will recur in the form of non metastatic biochemically relapsed prostate cancer (BRPC-M0). In these patients, PSA is rising while scans are negative for metastasis. Recent surveys demonstrated that approximately 40% of prostate cancer patients use various complementary and alternative medicine modalities as a component of therapy. Currently, there is no standard treatment for biochemical failure with proven benefits. Patients are being encouraged to enroll in clinical trials to help establish standards of care. Studies have shown that in 80% of patients with BRPC-M0, PSA will rise by at least 25% every 6 months.

Native pectin is a complex carbohydrate soluble fiber. Dietary fibers, such as pectin, have been shown to have positive effects on a wide spectrum of pathological conditions. Their positive influence on human health is explained by their antioxidative, hypocholesterolemic, and anticancer effects. MCP is composed of short, slightly-branched, carbohydrate chains derived from the soluble albedo fraction of citrus fruit peels, which have been altered by decreasing the molecular weight and degree of esterification using pH, temperature, and a controlled enzymatic process. This specific modification is critical as it allows for the absorption of MCP into the circulatory system and ensures its targeted bioactivity throughout the body. MCP is relatively rich in galactose and thus antagonizes the binding protein galectin-3 which results in suppression of cancer cell aggregation, adhesion, and metastasis. MCP acts as a ligand for galectin-3, which plays a major role in tumor formation and progression. It has been shown using a combination of fluorescence microscopy, flow cytometry, and atomic force microscopy, that pectin galactan specifically binds to the recombinant form of human galectin-3.

MCP showed anti-metastatic effects on cancer cells in multiple in vitro and in vivo studies. MCP inhibits carbohydrate mediated tumor growth, angiogenesis and metastasis via effects on galectin-3 function as demonstrated in an animal study on MCP's inhibition of breast and colon cancer progression. Results demonstrated a 70.2% reduction in breast tumor growth, a 66% reduction in breast angiogenesis, and 0% breast to lung metastasis compared to 100% in the control group; 0% colon to liver metastasis compared to 60% in the control group; and 25% colon to lymph metastasis compared to 100% in the control group. In an earlier study oral intake of MCP had been shown to act as a potent inhibitor of spontaneous prostate carcinoma metastasis in an animal model, demonstrating a significant 56% reduction in lung metastases. Human cancer cell lines (LNCaP androgen dependent \& PC3 androgen independent) and mouse prostate cancer cell lines (CASP2-1 androgen dependent and CASP1-1 androgen independent) treated with 1% MCP showed the following cytotoxicity due to induced apoptosis: 52.28% in LNCaP; 48.16% in PC3; 23.03% in CASP2-1; and 49.01% in CASP1-1.13 The effects of MCP on cell-cell and cell-matrix interactions mediated by carbohydrate-recognition were investigated by looking at MCP-inhibited B16-F1 melanoma cells adhesion and aggregation. MCP was shown to inhibit anchorage-independent growth of B16-F1 cells. These results indicate that carbohydrate-recognition by cell surface galectin-3 is involved in cell-extracellular matrix interaction and plays a role in anchorage-independent growth as well as the in vivo embolization of tumor cells. The modulation of the lung colonization of B16-F1 melanoma cells by MCP was first observed in 1992 when injection of MCP significantly decreased B16-F1 experimental metastasis (greater than 90%). Galectin-3 participation in the adhesion of the MDA-MB-435 cells to the endothelium was observed by the clustering of galectin-3 on endothelial cells at the sites of the contact with tumor cells, suggesting its potential functional significance for anti-adhesive therapy of cancer metastasis. The anti-metastatic effect of MCP has also been shown in reduced liver metastasis in a dose-dependent manner. The use of MCP in combination with the chemotherapy drug doxorubicin has demonstrated an increased cytotoxicity effect of inducing rapid cell death in prostate cancer cell lines DU-145 (androgen independent) through apoptosis, and in LNCaP (androgen dependant) through cell cycle arrest (G2-M arrest). These results show promise for the use of MCP with doxorubicin as an adjuvant to chemotherapy which may allow for lower dosage of the cancer drug to be used with less toxicity. A human clinical pilot trial with MCP showed an increase in prostate specific antigen doubling time, a marker of slowing the progression of prostate cancer. Clinical research on MCP also demonstrated a significant improvement in quality of life and stabilization of disease for patients with advanced solid tumors.

In addition to its therapeutic roles against cancer, MCP has been shown to remove toxic metals from the body without affecting essential minerals. In a clinical study, baseline levels of heavy metals and essential minerals were established with 24-hours urine collection prior to oral administration of MCP. 24-hours urine collection was repeated on days 1 and 6. Urinary excretion of lead, mercury, cadmium, and arsenic increased significantly, essential minerals were not changed significantly and no side effects were reported. In a hospital study in China, children with lead toxicity were given MCP. Their blood serum levels went down while corresponding lead levels in their urine increased significantly, without side effects.

MCP has immunostimulatory properties as demonstrated in human blood samples, including the activation of functional NK cells against K562 leukemic cells in culture: Unsaturated oligogalacturonic acids appear to be the immunostimulatory carbohydrates in MCP. Human blood samples collected from healthy volunteers were incubated with increasing concentrations of MCP and antibodies. After 24-hours, blood-antibody mix was lysed and run on a flow cytometer using a 3-color protocol and the % of activated T-cytotoxic cell subset, B-cell, and NK-cells, and % increase over untreated control calculated and a significant dose dependent activation was seen. The ability of the activated NK cells to induce leukemia cell death was analyzed by co-incubating MCP-treated lymphocytes with K562 T-cell leukemia cells and induced leukemia cell death was determined to be greater than 50%.

MCP has been demonstrated to be protective in experimental nephropathy with modulation of early proliferation and later galectin-3 expression, apoptosis and fibrosis by experimentally modulating galectin-3 in folic acid (FA)-induced acute kidney injury. Mice were pre-treated with normal or 1% MCP-supplemented drinking water one week before FA injection. During the initial injury phase, all FA treated mice lost weight whilst their kidneys enlarged secondary to the renal insult; these gross changes were significantly lessened in the MCP group but this was not associated with significant changes in galectin-3 expression. At a histological level, MCP clearly reduced renal cell proliferation but did not affect apoptosis. Later, during the recovery phase at two weeks, MCP-treated mice demonstrated reduced galectin-3 in association with decreased renal fibrosis, macrophages, proinflammatory cytokine expression and apoptosis. Galectin-3 inhibition by MCP was demonstrated to block Aldosterone (Aldo) induced collagen type I synthesis. Rats were treated with Aldo-salt combined MCP for 3 weeks. Hypertensive Aldo-treated rats presented vascular hypertrophy, inflammation, fibrosis, and increased aortic Gal-3 expression. MCP treatment reversed all the above effects.

MCP is affirmed as GRAS (generally regarded as safe) under the US Code of Federal Regulation 21CFR184.1588.

Dietary Supplement: PectaSol-C Modified Citrus Pectin (MCP) Oral administration of PectaSol-C MCP (4.8 grams in six capsules three times a day away from food).

Effect of Modified Citrus Pectin on PSA Kinetics in Biochemical Relapsed PC With Serial Increases in PSA

Phase III, Single-Center, Open Label, Trial Evaluating the Safety and Efficacy of PectaSol-C Modified Citrus Pectin on PSA Kinetics in Prostate Cancer in the Setting of Serial Increases in PSA

At baseline (0 month), and end of study (6 month): Blood draw for serum levels of galectin-3, C-reactive protein, and lipid panel.

PSA doubling time increase will be used to show effectiveness of the Modified Citrus pectin (MCP).

Patient tolerability of MCP will be assessed by comparing the results of weekly self-assessment diaries with baseline assessments.

EcoNugenics

Symptoms and General Pathology

Recurrence

All Drugs and Chemicals

Vaccines

Monatide (IMS 3015)

Total of 12 SC vaccinations with RV001V. The first 6 vaccinations (priming period) will be given every 2 weeks, and then the following 5 vaccinations (7 through 11) will be administered with 4 weeks between each vaccination (Maintenance period), and the last vaccination (12th) will be administered 6 months following the 11th vaccination (boosting injection).

Total of 12 SC vaccinations with placebo. The first 6 vaccinations (priming period) will be given every 2 weeks, and then the following 5 vaccinations (7 through 11) will be administered with 4 weeks between each vaccination (Maintenance period), and the last vaccination (12th) will be administered 6 months following the 11th vaccination (boosting injection).

RV001V consists of the peptide RV001 and the adjuvant Montanide ISA 51. RV001 Vaccine 0.1 mg/mL (RV001V).

RV001V

Placebo consist of the vaccine vehicle and the adjuvant Montanide ISA 51. Placebo

Placebo

Klaus Brasso, MD

This Phase II trial will enroll approximately 180 adult male patients with an earlier histologic diagnosis of prostatic adenocarcinoma and a biochemical recurrence (BCR) within 3 years of radical prostatectomy (RP) or definitive RT and no distant metastasis or locoregional recurrence. The trial is a randomized placebo-controlled double-blind study of a peptide cancer vaccine (RV001V).

Study of RV001V in Biochemical Failure Following Curatively Intended Therapy For Localized Prostate Cancer

A Phase 2, Double-Blind, Placebo Controlled Study of RV001V in Men With Biochemical Failure Following Curatively Intended Therapy For Localized Prostate Cancer (BRaVac)

Time to PSA progression is defined as the time from randomization to doubling of PSA from the baseline value. The time to doubling will be estimated from a log-linear regression of PSA values.

The numbers and proportions of patients with any treatment-emergent adverse event (TEAE), and any serious TEAE will be summarized

time from randomization to documented clinical recurrence (distant or local), or death from any cause, censoring at date of last follow-up (FU)

RhoVac APS

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Disease Attributes

Anti-Inflammatory Agents

Antineoplastic Agents

Antiemetics

Gastrointestinal Agents

Anti-Infective Agents

Dexamethasone

Prednisone

Lenalidomide

Dexamethasone acetate

Vorinostat

BB 1101

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

HIV Protease Inhibitors

Protease Inhibitors

Enzyme Inhibitors

Immunologic Factors

Angiogenesis Inhibitors

Growth Inhibitors

Histone Deacetylase Inhibitors

Patients, who are receiving Lenalidomide maintenance treatment with or without prednisone, will be randomized to receive:

Cohort 1: ZLd association:

* Lenalidomide orally at the dose of 25 mg/day for 21 days every 28 days
* Vorinostat orally at the dose of 400 mg/day on days 1-7 and 15- 21 on a 28-day cycle.
* Dexamethasone orally at the dose of 40 mg day 1,8, 15, 22 every 28 days.

Patients, who are receiving Lenalidomide maintenance treatment with or without prednisone, will be randomized to receive: Lenalidomide orally at the dose of 25 mg/day for 21 days every 28 days

• Dexamethasone orally at the dose of 40 mg day 1,8, 15, 22 every 28 days.

Vorinostat orally at the dose of 400 mg/day on days 1-7 and 15- 21 on a 28-day cycle

Lenalidomide orally at the dose of 25 mg/day for 21 days every 28 days

Dexamethasone orally at the dose of 40 mg day 1,8, 15, 22 every 28 days.

Antonio Palumbo, MD

Histone deacetylase (HDAC) inhibitors represent a potential new class of antitumor agents. Vorinostat (suberoylanilide Hydroxamic acid, SAHA) inhibits the activity of all 11 known human class I and II HDACs. HDACs have many protein targets whose structure and function are altered by acetylation, including histones and non-histones proteins component of transcription factors controlling gene expression and proteins that regulate cell proliferation, migration and death (1). Vorinostat has undergone initial evaluation in several phase I and II clinical trials in both solid and hematologic malignancies. It has shown activity in hematologic malignancies including Hodgkin's disease and non Hodgkin's lymphomas (2-5); it has been approved for treatment of cutaneous manifestation in patients with primary cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies (6). HDAC function is critical for Multiple Myeloma (MM) cells by actively maintaining a transcriptional program indispensable for their uncontrolled proliferation and/or inappropriate resistance to pro-apoptotic stimuli. The pleiotropic anti-MM effects of Vorinostat and its ability to sensitize MM cellsto multiple conventional or novel agents (7) provide the framework for clinical trials of Vorinostat in MM. A phase I trial of oral Vorinostat alone in advanced MM shows modest activity, but treatment was generally well tolerated (common drug related adverse events (AEs) included fatigue, anorexia, dehydration, diarrhea and nausea and were mostly grade \< 2) (8). A phase I clinical trial of Vorinostat in association with Bortezomib in relapsed MM patients report a partial response (PR) rate of 42%, with responses occurring also in patients refractory to a previous Bortezomib based regimen. Treatment was generally well tolerated (main adverse events were myelosuppression, fatigue and diarrhea) (9). Lenalidomide is an active agent against MM, that as shown activity in both the relapse and newly diagnosed settings, in combination with chemotherapy or steroids only. The dose of Lenalidomide commonly used in the relapse setting, in association with steroids, is 25 mg/day on days 1-21 every 28 days (10, 11). A recent phase I study evaluated the safety and tolerability of Vorinostat in combination with Lenalidomide and Dexamethasone in relapsed patients:no dose limiting toxicities prohibited dose escalation, the maximum tolerated dose has not been reached and the maximum administered dose was Lenalidomide 25 mg/day on days 1-21, Dexamethasone 40 mg/day on days 1,8,15,22, Vorinostat 400 mg/day on days 1-7 and 15-21; each cycle was repeated every 28 days. Rate of at least PR was 51%, and activity was seen also in patients who received prior Lenalidomide therapy (clinical benefit reported in 69% of patients, including minimal response or better in 33% of Lenalidomide refractory patients). The most common drug related grade \> 3 AEs were neutropenia, thrombocytopenia, diarrhea, anemia and fatigue (12). Since Vorinostat has shown efficacy also in patients previously treated with Lenalidomide, and in patients refractory to Lenalidomide, the investigators hypothesis is that the addition of Vorinostat and low-dose dexamethasone to Lenalidomide (ZLd), in patients experiencing a biochemical relapse during a Lenalidomide maintenance ongoing therapy, can overcome Lenalidomide-drug resistance and result in a significant response rate, that can translate into a significant improvement in survival of MM patients. The second hypothesis is that, since the dose of Lenalidomide commonly administered in maintenance therapy, is 10 mg days 1-21 every 28 days, the increase in Lenalidomide dose to the standard dose used for relapsing patients, plus low-dose Dexamethasone (Ld), in patients experiencing a biochemical relapse during a Lenalidomide ongoing maintenance, can as well overcome Lenalidomide-drug resistance and determine a significant response rate, that can translate into a significant improvement in survival of MM patients.

This is a multicenter non comparative, randomized, open label, phase II study. Patients, who are receiving Lenalidomide maintenance treatment with or without prednisone, will be randomized to receive:

Cohort 1: ZLd association:

Lenalidomide orally at the dose of 25 mg/day for 21 days every 28 days Vorinostat orally at the dose of 400 mg/day on days 1-7 and 15- 21 on a 28-day cycle.

Dexamethasone orally at the dose of 40 mg day 1,8, 15, 22 every 28 days.

Cohort 2: Ld association:

Lenalidomide orally at the dose of 25 mg/day for 21 days every 28 days Dexamethasone orally at the dose of 40 mg day 1,8, 15, 22 every 28 days.

Patients must have a -confirmed diagnosis of relapsed multiple myeloma. In this Phase II study, a total of up to 35 patients in the ZLd cohort and 48 in the Ld cohort will be enrolled. It is anticipated that full accrual to this study will take approximately 36 months.

Vorinostat Plus Lenalidomide and Dexamethasone or Lenalidomide Plus Dexamethasone in Multiple Myeloma Patients Who Experience Biochemical Relapse During Lenalidomide Maintenance Therapy

A Phase II, Multi-center, Open-label, Randomized Study of Vorinostat Plus Lenalidomide and Dexamethasone or Lenalidomide Plus Dexamethasone in Multiple Myeloma Patients Who Experience Biochemical Relapse During Lenalidomide Maintenance Therapy

Determine the rate of PR with the association of ZLd and Ld in patients who experience biochemical relapse during Lenalidomide maintenance therapy. ZLd and Ld: responses will be evaluated after the enrollment of 10 and 18 pts respectively. If ≤1 and ≤2 respectively responses will be observed the trial will be stopped. Otherwise 19 and 25 pts respectively will be enrolled: if ≤5 for Zld and ≤7 for Ld responses will be observed, no further investigation will be needed

The occurrence of progression will determine the duration of PFS.

The occurence of death will determine the OS

Tiziana Marangon

Sponsor

Antirheumatic Agents

Cyclophosphamide

Pomalidomide

Myeloma Proteins

Paraproteins

Immunosuppressive Agents

Antineoplastic Agents, Alkylating

Alkylating Agents

Patients will receive treatment at biochemical relapse with pom-dex Pomalidomide: 4 mg/day on days 1-21 Dexamethasone: 40 mg on days 1, 8, 15, 22 For 28-day cycles until progression or intolerance

Patients will receive treatment at biochemical relapse with pom-cyclo-dex Pomalidomide: 4 mg/day on days 1-21 Cyclophosphamide: 50 mg every other day Dexamethasone: 40 mg on days 1, 8, 15, 22 For 28-day cycles until progression or intolerance

Patients will be randomized at biochemical relapse and they will start treatment with pom-dex at the onset of CRAB symptoms/significant paraprotein increase.

Pomalidomide: 4 mg/day on days 1-21 Dexamethasone: 40 mg on days 1, 8, 15, 22 For 28-day cycles until progression or intolerance

Patients will be randomized at biochemical relapse and they will start treatment with pom-cyclo-dex at the onset of CRAB symptoms/significant paraprotein increase.

Pomalidomide: 4 mg/day on days 1-21 Cyclophosphamide: 50 mg every other day Dexamethasone: 40 mg on days 1, 8, 15, 22 For 28-day cycles until progression or intolerance

4 mg/daily as oral administration (PO) on days 1-21.

50 mg every other day as oral administration (PO) on days 1-28

40 mg as oral administration (PO) on days 1, 8, 15, 22.

The combination lenalidomide plus low-dose dexamethasone (Rd) is an active treatment for Multiple Myeloma (MM) patients, both at diagnosis and at relapse.

Pomalidomide, is an immunomodulatory molecule (IMID), derivative of thalidomide, developed to improve the efficacy and reduce the toxicity of the parent molecule. Pomalidomide and dexamethasone (pom-dex) proved to be an effective and safe treatment in MM patients refractory to lenalidomide and refractory/intolerant to bortezomib.

The addition of chemotherapy to novel drugs has been evaluated both at diagnosis and at relapse. The combination of pomalidomide-cyclophosphamide-prednisone proved to be safe and effective in relapsed/refractory MM patients. The combination pomalidomide-cyclophosphamide-dexamethasone (pom-cyclo-dex) was tested in a phase II study in patients with relapsed and refractory MM, demonstrating a good tolerability using pomalidomide at the dose of 4 mg. Pom-cyclo-dex resulted in a superior response rate and Progression-Free Survival (PFS) compared to pom-dex. The increased hematologic toxicities, as a result of the addition of oral cyclophosphamide, were manageable. With an overall response rate of 65% the combination demonstrated a promising efficacy.The first aim of our trial, is to compare the combination of pom-cyclo-dex vs pom-dex.

Relapsed myeloma is defined as previously treated myeloma that progresses and requires the initiation of salvage therapy.

According to International Myeloma Working Group (IMWG) recommendation, biochemical relapse is defined as an increase of ≥ 25% of tumor burden from lowest value, without any CRAB feature (CRAB is defined as the onset of clinical symptoms: hypercalcemia, renal failure, anemia and bone lesions) and detected in 2 consecutive determinations.

Clinical relapse requires one or more direct indicators of progressive disease and end organ dysfunction (CRAB features).

Treatment at relapse should start in case of clinical relapse or a significant paraprotein increase (doubling of M-component in 2 months).

In case of biochemical relapse the standard is observation only, as in case of asymptomatic MM at diagnosis.

However, a recently published trial, showed improved PFS and OS for newly diagnosed asymptomatic patients treated with lenalidomide and dexamethasone in comparison with observation only. Our hypothesis is that similarly, in the relapse setting, patients may benefit from an early intervention, meaning a treatment at biochemical relapse and not only in case of clinical relapse or rapid increase of M-component.

Multiple myeloma (MM) is a neoplastic disease of older adults, with a higher incidence in elderly patients: 26% are aged 65-74 years, and 37% are older than 75 years. The annual prevalence of MM is approximately 31 cases per 100,000 people in patients aged 65-74 years, and it increases to 46 cases per 100,000 people in patients aged ≥75 years. The prevalence of myeloma is likely to increase due to the extended survival and the growing life expectancy of the general population.

Recently, the introduction of novel agents such as thalidomide, lenalidomide, pomalidomide and bortezomib, has changed the treatment paradigm of MM and extended survival.

The prognosis of patients who are refractory to novel agents is especially poor. A retrospective study has recently demonstrated that patients with relapsed MM, who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive treatment with an IMiD, had a median overall survival (OS) and event free survival (EFS) of 9 and 5 months, respectively.

STUDY DESIGN When patients experience biochemical relapse during lenalidomide maintenance, they will stop lenalidomide, as established in the related experimental protocol. Afterwards, patients can be considered for the enrollment in the present study if all inclusion and exclusion criteria are met.

This is a multicenter, randomized, open label phase III study designed to assess the safety and the efficacy of two different pomalidomide combinations as salvage treatment in multiple myeloma (MM) patients.

Patients will be evaluated at scheduled visits in up to 3 study periods: pre-treatment, treatment and long-term follow-up (LTFU).

The pre-treatment period includes screening visits, performed at study entry. After providing written informed consent to participate in the study, patients will be evaluated for study eligibility. The screening period includes the availability of inclusion criteria described above.

The treatment period includes administration of pomalidomide and dexamethasone in arm A and pomalidomide combined with cyclophosphamide and dexamethasone in arm B. The response will be assessed after each cycle. Patients will be randomized to receive treatment at biochemical relapse (ARM I) or at clinical relapse (ARM II).

The LTFU periods will start after development of confirmed progression disease (PD), all patients are to be followed for survival during the LTFU period every 3 months via telephone or office visit.

This is a 2x2 factorial randomized study.

Pom-dex Versus Pom-Cyclo-dex in MM Patients With Biochemical or Clinical Relapse, During Lena Maintenance Treatment

A MULTICENTER, OPEN LABEL, RANDOMIZED PHASE III STUDY OF POMALIDOMIDE-DEXAMETHASONE vs POMALIDOMIDE-CYCLOPHOSPHAMIDE-DEXAMETHASONE IN MULTIPLE MYELOMA (MM) PATIENTS WHO EXPERIENCE BIOCHEMICAL OR CLINICAL RELAPSE DURING LENALIDOMIDE MAINTENANCE TREATMENT

defined as the time from the date of random disclosure to the date of death from any cause for the comparisons B vs A

defined as the time from the date of random disclosure to the date of death from any cause for the comparisons II vs I

defined as the time from random assignment to the early or late strategy to the date of onset of CRAB symptoms or death.

Clinical relapse requires one or more direct indicators of progressive disease and end organ dysfunction (CRAB features). Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder:

* hypercalcaemia
* renal insufficiency
* anaemia
* bone lesions

Any one or more of the following biomarkers of malignancy:

* clonal bone marrow plasma cell percentage ≥60%
* involved:uninvolved serum free light chain ratio ≥100
* \>1 focal lesions on MRI studies (each focal lesion must be 5 mm or more in size)

Progresson was defined accoring to IMWG criteria as reported before

PFS for the comparison B vs A will be measured from the date of randomization disclosure to the date of first observation of PD, or death from any cause as an event. Subjects who have not progressed or who withdraw from the study will be censored at the time of the last complete disease assessment. All subjects who were lost to Follow Up (FU) will also be censored at the time of last complete disease assessment

PFS for the comparison II vs I will be measured from the date of randomization disclosure to the date of first observation of PD, or death from any cause as an event. Subjects who have not progressed or who withdraw from the study will be censored at the time of the last complete disease assessment. All subjects who were lost to FU will also be censored at the time of last complete disease assessment

PFS for the comparison B vs A will be measured from the date of randomization disclosure to the date of first observation of PD in second line therapy, or death from any cause as an event. Subjects who have not progressed or who withdraw from the study will be censored at the time of the last complete disease assessment. All subjects who were lost to FU will also be censored at the time of last complete disease assessment

PFS for the comparison II vs I will be measured from the date of randomization disclosure to the date of first observation of PD in second line therapy, or death from any cause as an event. Subjects who have not progressed or who withdraw from the study will be censored at the time of the last complete disease assessment. All subjects who were lost to FU will also be censored at the time of last complete disease assessment

in terms of partial response (PR), very good partial response (VGPR), complete response (CR).and stringent complete response (sCR) according to IMWG response crieria (https://www.myeloma.org/resource-library/international-myeloma-working-group-imwg-uniform-response-criteria-multiple).

outcome will be measured with EORTC-QLQ-C30 at baseline, every 2 months during the first year, and then every 6 months for the comparison B vs B and I vs II.

outcome will be measured with QLQ-MY24 at baseline, every 2 months during the first year, and then every 6 months for the comparison B vs B and I vs II.

Fondazione EMN Italy Onlus

In the table "Other Adverse Events" each term reports ae term_ctcae grade

Patients will receive treatment at biochemical relapse with pom-dex Pomalidomide: 4 mg/daily as oral administration (PO) on days 1-21. Dexamethasone: 40 mg as oral administration (PO) on days 1, 8, 15, 22. For 28-day cycles until progression or intolerance

ARM Pom-dex Early (A-I)

Patients will be randomized at biochemical relapse and they will start treatment with pom-dex at the onset of CRAB symptoms/significant paraprotein increase.

Pomalidomide: 4 mg/daily as oral administration (PO) on days 1-21. Dexamethasone: 40 mg as oral administration (PO) on days 1, 8, 15, 22. For 28-day cycles until progression or intolerance

ARM Pom-dex Late (A-II)

Patients will receive treatment at biochemical relapse with pom-cyclo-dex Pomalidomide: 4 mg/daily as oral administration (PO) on days 1-21. Cyclophosphamide: 50 mg every other day as oral administration (PO) on days 1-28 Dexamethasone: 40 mg as oral administration (PO) on days 1, 8, 15, 22. For 28-day cycles until progression or intolerance

ARM Pom-cyclo-dex Early (B-I)

Patients will be randomized at biochemical relapse and they will start treatment with pom-cyclo-dex at the onset of CRAB symptoms/significant paraprotein increase.

Pomalidomide: 4 mg/daily as oral administration (PO) on days 1-21. Cyclophosphamide: 50 mg every other day as oral administration (PO) on days 1-28 Dexamethasone: 40 mg as oral administration (PO) on days 1, 8, 15, 22. For 28-day cycles until progression or intolerance

ARM Pom-cyclo-dex Late (B-II)

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Caucasian

Race/Ethnicity, Customized

Italy

Region of Enrollment

Eastern Cooperative Oncology Group (ECOG) Performance Status

isotype

International Staging System (ISS) for Multiple Myeloma Stage VALUES (β2M = Serum β2 microglobulin; ALB = serum albumin I β2M \< 3.5 mg/L; ALB ≥ 3.5 g/dL II β2M \< 3.5 mg/L; ALB ≥ 3.5 g/dL; or β2M 3.5 - 5.5 mg/L III β2M \> 5.5 mg/L I low risk, II medium risk, III high risk

International Staging System (ISS) Stage

ASCT

Bort

Previous Therapies (induction/Autologous Stem Cell Transplantation/consolidation)

This analysis included only patients in whom CPd vs Pd randomization was disclosed; 1pt randomized to Late (II) treatment who not achieved a CRAB has not the disclosure of the randomization between A vs B arm..

Main limitations is that the sample size of participants needed to achieve target power and statistically reliable results was not reach. And no statistical testing was performed.

Death

Censored

Arm A

Arm B

This analysis included only patients in whom CPd vs Pd randomization was disclosed.

Overall Survival (OS)

Arm I

Arm II

Overall Survival

Clinical Progression

Progression Free-survival (PFS)

Progression Free Survival (PFS)

Progression Free-survival 2(PFS2)

Progression Free Survival 2(PFS2)

Objective Overall Response Rate for the Comparison B vs A

Objective Overall Response Rate for the Comparison II vs I

ARM A-I

ARM A-II

ARM B-I

ARM B-II

data could not be reported in the data table since analysis was not performed according to the lower sample size and QLQ missing

Quality of Life Questionnaire (QLQ) With EORTC-QLQ-C30

Quality of Life With QLQ-MY(Myeloma)24

Overall Study

Behaviors and Mental Disorders

Quality of Life

Central Nervous System Depressants

Anesthetics

A consecutive sample of clinically localized prostate cancer patients treated with radical prostatectomy, external beam radiotherapy and prostate brachytherapy in 10 Spanish hospitals.

quality of life assessed by the Expanded Prostate Cancer Index Composite (EPIC), the Medical Outcomes Study 36-Item Short Form (SF-36) version 2, the Functional Assessment of cancer Therapy, General and Prostate specific (FACT-G and FACT-P, respectively), the International Prostate Symptom Score (IPSS), and the International Index of Erectile Function (IIES). Quality of Life questionnaires are administered centrally by telephone interview before treatment and during follow-up at 1, 3, 6, and 12 months after treatment the first year, then annually until 10 years, and every 5 years thereafter.

Demographic and clinical characteristics at baseline are recorded at clinical sites and include age, Prostate Specific Antigen (PSA), Gleason grading, prostate volume, risk group and use of neoadjuvant hormonal treatment. According tho the national health guidelines participants are visited every 6-12 months after treatment.

Quality of life assessment and Clinical evaluation

The surgery group underwent radical retropubic prostatectomy. The surgery is performed by a technique based on a modification of the radical retropubic prostatectomy described by Walsh. The prostatectomy is performed in retrograde way, preserving the neurovascular bundles if feasible, controlling the vessels with titanium clips, and avoiding any kind of coagulation to decrease the risk of neurovascular bundle damage. The bladder neck may be preserved on surgeon criteria. Lymph node dissection is rarely performed due to the extremely low risk of metastatic involvement in this subset of patients. The operative time is about 2 to 3 hours and required hospital stay. The patient has a urinary catheter placed for 1 to 3 weeks to facilitate bladder emptying.

Radical retropubic prostatectomy surgery

External beam radiation is carried out with the 3D conformal technique. Patients are treated in a supine position by immobilizing feet and legs. Data from a computed tomography (CT) scan performed with the patient in the treatment position were entered into a 3D treatment-planning system to outline prostate, bladder, and rectum on each slice. Seminal vesicles and regional lymphatics are also contoured if a high risk of involvement was suspected. Applied margins are used to calculate prostate planning target volume (PTV). Custom blocking with Cerrobend blocks or multileaf collimators are designed using beam's eye view, and additional margins were adjusted to provide a minimum dose of 95% to the prostate PTV. Treatment is delivered in 1.8 to 2.0 Gy daily fractions, 5 days per week. Off-line setup control is assessed weekly by comparing orthogonal portal images with the corresponding digitally reconstructed radiographs.

External beam radiotherapy

Brachytherapy is performed by pre-planned procedure. Under epidural anaesthesia, the patient is placed in the lithotomy position (forced lithotomy position larger prostate volumes) and, after probing the patient, the best prostate spatial location is searched, proceeding then to prepare the sterile field and bladder catheterization. A prostate volumetry with a three-dimensional reconstruction is performed and automatically transferred to the scheduler, which processes the images and outlines the prostate, urethra and rectum in each of the sections. In LDR prostate brachytherapy, the prostate gland corresponds to the PTV. The standard dose for 100% isodose is 145 Gy according to the TG-T43 for I-125 sources. Dosimetry calculation of the automatically prescribed dosage is then estimated, with a final manual optimization.

Prostate Brachytherapy

Montserrat Ferrer Fores, PhD, MD

The purpose of this study is to evaluate the effectiveness of the three most established primary treatments for patients with clinically localized prostate cancer (radical prostatectomy, external-beam radiotherapy, and prostate brachytherapy) at short, mid and long-term follow-up. The primary aim is assessing Quality of Life impact of treatments' side effects. As secondary objectives biochemical disease-free survival, overall survival, and prostate cancer-specific survival will be also assessed.

Primary Objective:

To assess the Quality of Life impact of treatments' side effects (radical prostatectomy, external beam radiotherapy and prostate brachytherapy) on patients with localized prostate cancer at short, mid and long-term follow-up.

Secondary Objectives:

* To assess biochemical disease-free survival by treatment and risk group, at mid and long-term follow-up.
* To assess overall survival by treatment and risk group, at mid and long-term follow-up.
* To assess prostate cancer-specific survival by treatment and risk group, at long-term follow-up.
* To assess disease-free survival by treatment and risk group, at long-term follow-up.
* To assess perceived general health and cancer-specific quality of life by treatment and risk group, at short, mid and long-term follow-up.
* To calculate the resource use and cost of the three primary treatments.
* To assess preferences with direct and indirect methods.

Outline:

This is a prospective observational study of a cohort with clinically localized prostate cancer treated with either radical retropubic prostatectomy, three-dimensional external-beam radiotherapy, or interstitial brachytherapy.

Participants are consecutively recruited in 10 Spanish hospital departments (located in five autonomous communities). Patients eligible for inclusion were those in stage T1 or T2, treated in one of the participating centers and without previous prostate transurethral resection. Patients are staged according to the 1992 American Joint Committee on Cancer clinical staging guidelines using a directed history and physical examination. The decision regarding treatment is made jointly by patients and health professionals.

Demographic and clinical characteristics at baseline are recorded at clinical sites and include age, Prostate Specific Antigen (PSA), Gleason grading, prostate volume, risk group and use of neoadjuvant hormonal treatment. According tho the national health guidelines participants are visited every 6-12 months after treatment.

Quality of Life questionnaires are administered centrally by telephone interview before treatment and during follow-up at 1, 3, 6, and 12 months after treatment the first year, then annually until 10 years, and every 5 years thereafter. Quality of Life evaluations are gathered using computer-assisted telephone administration and include: (1) the Expanded Prostate Cancer Index Composite (EPIC), specifically designed to measure the impact of the different treatments; (2) SF-36 Health Survey Questionnaire; (3) Functional Assessment of cancer Therapy, General and Prostate specific (FACT-G and FACT-P, respectively); (4) International Prostate Symptom Score (IPSS); and (5) International Index of Erectile Function (IIES).

A total of 120 patients was calculated to be required in each treatment group to detect between-treatment group differences of 5-points on the urinary irritative-obstructive score of the EPIC questionnaire given a standard deviation of 18.99 and a statistical power of at least 80% at a significance level of 5%, with an expected loss to follow-up of 10%. The analyst is blinded to treatment assignation.

Effectiveness of Localized Prostate Cancer Treatments

Effectiveness of Three Primary Treatments for Localized Prostate Cancer: Radical Prostatectomy, External-beam Radiotherapy, and Prostate Brachytherapy

The Expanded Prostate Cancer Index Composite (EPIC) is a prostate cancer specific questionnaire constructed by expanding the UCLA-PCI to assess function and bother in the 4 domains: Urinary, Bowel, Sexual, and Hormonal.For each domain a summary score is constructed. In addition, two urinary scales that distinguish irritative/obstructive symptoms and incontinence are developed by the authors of the questionnaire. The 50 EPIC items are answered on a 5-point Likert scale and these are transformed linearly to obtain scores ranging from 0-100, with higher scores indicating better Quality of Life.

Number of participants who are free of biochemical relapse after a specified duration of time. Biochemical relapse is measured by PSA levels. For patients treated with radical prostatectomy, biochemical relapse criteria of the American Urological Association is applied, and for patients treated with external radiotherapy or brachytherapy, criteria of the American Society for Therapeutic Radiology and Oncology is followed.

Number of participants who are alive after a specified duration of time. Vital status and data of death from any cause recorded by linkage with the National Institute of Statistics.

Number of participants who are not dead due to prostate cancer after a specified duration of time. Death due to prostate cancer according to the cause of death registered in the the National Institute of Statistics.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Effect of Modified Citrus Pectin on PSA Kinetics in Biochemical Relapsed PC With Serial Increases in PSA	NCT01681823	Prostatic Neopl...	PectaSol-C Modi...	21 Years -	EcoNugenics
Study of RV001V in Biochemical Failure Following Curatively Intended Therapy For Localized Prostate Cancer	NCT04114825	Prostate Cancer...	RV001V Placebo	18 Years -	RhoVac APS
Vorinostat Plus Lenalidomide and Dexamethasone or Lenalidomide Plus Dexamethasone in Multiple Myeloma Patients Who Experience Biochemical Relapse During Lenalidomide Maintenance Therapy	NCT01501370	Multiple Myelom...	Vorinostat Lenalidomide Dexamethasone Lenalidomide Dexamethasone	18 Years -	University of Turin, Italy
Vorinostat Plus Lenalidomide and Dexamethasone or Lenalidomide Plus Dexamethasone in Multiple Myeloma Patients Who Experience Biochemical Relapse During Lenalidomide Maintenance Therapy	NCT01501370	Multiple Myelom...	Vorinostat Lenalidomide Dexamethasone Lenalidomide Dexamethasone	18 Years -	University of Turin, Italy
Pom-dex Versus Pom-Cyclo-dex in MM Patients With Biochemical or Clinical Relapse, During Lena Maintenance Treatment	NCT03440411	Multiple Myelom...	Pomalidomide Cyclophosphamid... Dexamethasone	18 Years - 80 Years	Fondazione EMN Italy Onlus
Effectiveness of Localized Prostate Cancer Treatments	NCT01492751	Prostate Cancer	Quality of life... Radical retropu... External beam r... Prostate Brachy...	-	Fundacion IMIM
Early Salvage Therapy for Patients With Advanced Features for Biochemical Relapse After Radical Prostatectomy for Localized Prostate Carcinoma In Correlation With Supposed Molecular-genetic Parameters of Higher Aggressiveness	NCT05232578	Prostate Cancer	Early salvage r... Delayed Salvage...	18 Years -	General University Hospital, Prague

Spots Global Cancer Trial Database for biochemical relapse