Alvocidib and Oxaliplatin With or Without Fluorouracil and Leucovorin Calcium in Treating Patients With Relapsed or Refractory Germ Cell Tumors

Study Overview
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Brief Summary
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This phase II trial is studying alvocidib and oxaliplatin to see how well they work when given with or without fluorouracil and leucovorin calcium in treating patients with relapsed or refractory germ cell tumors. Drugs used in chemotherapy, such as alvocidib, oxaliplatin, fluorouracil, and leucovorin calcium, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving alvocidib together with oxaliplatin with or without fluorouracil and leucovorin calcium may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the antitumor efficacy of the combination of flavopiridol and oxaliplatin with or without 5-FU and leucovorin in patients with relapsed or refractory GCT. The necessity of 5-FU and leucovorin to the combination will also be indirectly tested in this study. SECONDARY OBJECTIVES: I. To further evaluate the safety of flavopiridol in combination with oxaliplatin with or without 5-fluorouracil and leucovorin in patients with refractory or relapsed GCT. II. To evaluate the time to tumor response (TTR) and progression-free survival for patients with refractory or relapsed GCT treated with flavopiridol in combination with oxaliplatin with or without 5-fluorouracil and leucovorin. III. To explore the association between treatment response and p21, p53 and apoptotic markers. OUTLINE: Patients are initially enrolled in part A (closed to accrual as of 11/15/2010). Depending on response to treatment, additional patients may be enrolled in part B. PART A (alvocidib and oxaliplatin) (closed to accrual as of 11/15/2010): Patients receive alvocidib IV over 1 hour and oxaliplatin IV over 2 hours on days 1, 15, and 29. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity. PART B (alvocidib and FOLFOX): Patients receive alvocidib IV over 1 hour, oxaliplatin IV over 2 hours, and leucovorin calcium IV over 2 hours followed by fluorouracil IV continuously over 48 hours on days 1, 15, and 29. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity. Tumor tissue samples may be collected periodically for further laboratory analysis. After completion of study treatment, patients are followed up every 4-8 weeks.

Official Title
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A Non-randomized Phase 2 Study of Alvocidib (Flavopiridol) Plus Oxaliplatin With or Without 5-FU and Leucovorin for Relapsed or Refractory Germ-Cell Tumors

Conditions
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Recurrent Extragonadal Seminoma, Recurrent Malignant Extragonadal Germ Cell Tumor, Recurrent Malignant Extragonadal Non-Seminomatous Germ Cell Tumor, Recurrent Malignant Testicular Germ Cell Tumor, Recurrent Ovarian Germ Cell Tumor, Stage III Testicular Cancer, Stage IV Extragonadal Non-Seminomatous Germ Cell Tumor, Stage IV Extragonadal Seminoma, Stage IV Ovarian Germ Cell Tumor

Intervention / Treatment
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* Drug: Alvocidib Hydrochloride
* Drug: Fluorouracil
* Drug: Leucovorin Calcium
* Drug: Oxaliplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed germ cell tumor (GCT) Seminoma or non-seminoma Progressive disease after prior cisplatin-based therapy AND meets 1 of the following criteria: Not considered to be a candidate for potentially curative therapy Previously treated with high-dose chemotherapy regimens Does not wish to undergo potentially curative high-dose therapy Measurable or evaluable disease, as defined by 1 of the following criteria: Unidimensionally measurable metastatic disease, defined as ≥ 1 malignant tumor mass that can be accurately measured in ≥ 1 dimension as ≥ 20 mm by conventional CT scan or MRI or as ≥ 10 mm by spiral CT scan Bone lesions, ascites, peritoneal carcinomatosis, miliary lesions, pleural or pericardial effusions, lymphangitis of the skin or lung, cystic lesions, or irradiated lesions are not considered measurable disease Patients with measurable disease only (i.e., normal tumor markers) must have ≥ 1 site of disease that has not been previously irradiated Elevation of alpha-fetoprotein > 15 ng/mL and/or elevation of beta-human chorionic gonadotropin > 2.2 mIU/L If tumor markers are not elevated, ≥ 1 site of measurable disease must be present No known untreated CNS metastasis or primary CNS tumor Patients who have undergone local treatment for brain metastases and whose brain metastases are demonstrated to be stable by repeat imaging studies performed ≥ 4 weeks after treatment are eligible Karnofsky performance status 70-100% ANC ≥ 1,000/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 8.0 g/dL Serum creatinine ≤ 2.0 times upper limit of normal (ULN) Total serum bilirubin ≤ 1.5 times ULN AST and ALT ≤ 2.5 times ULN (unless elevation is due to underlying malignancy) Not pregnant or nursing Negative pregnancy test by ultrasound Fertile patients must use effective contraception Willing and able to comply with scheduled study visits, treatment plans, laboratory tests, follow-up tests for safety or effectiveness, and other study procedures Mediport or Broviac access required for patients enrolled in part B of the study No serious active infections No significant (≥ grade 2) or persistent ongoing toxicity, including peripheral neuropathy, from prior therapy None of the following within the past 6 months: Myocardial infarction Severe/unstable angina Coronary/peripheral artery bypass graft Symptomatic congestive heart failure Cerebrovascular accident or transient ischemic attack Pulmonary embolism No contraindication to any of the study drugs No other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, interfere with the interpretation of study results, and, in the judgement of the investigator, may make the patient inappropriate for study entry No concurrent anti-retroviral therapy for HIV-positive patients Recovered from prior radiotherapy or surgery Residual grade 1 toxicities allowed No prior alvocidib At least 2 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C), immunotherapy, or radiotherapy More than 4 weeks since prior major surgery No other concurrent approved or investigational anticancer treatment, including surgery, radiotherapy, chemotherapy, biologic-response modifiers, hormone therapy, or immunotherapy No concurrent participation in another investigational treatment clinical trial Concurrent participation in supportive care trials or non-treatment trials (e.g., quality of life or laboratory analysis studies) allowed No concurrent vitamins, antioxidants, herbal preparations, or supplements, except for a single-tablet multivitamin

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A (alvocidib and oxaliplatin)<br>Patients receive alvocidib IV over 1 hour and oxaliplatin IV over 2 hours on days 1, 15, and 29. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity. | Drug: Alvocidib Hydrochloride<br>* Given IV<br>* Other names: MDL-107826A;Drug: Oxaliplatin<br>* Given IV<br>* Other names: SR-96669;|
| Experimental: Part B (alvocidib and FOLFOX)<br>Patients receive alvocidib IV over 1 hour, oxaliplatin IV over 2 hours, and leucovorin calcium IV over 2 hours followed by fluorouracil IV continuously over 48 hours on days 1, 15, and 29. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity. | Drug: Alvocidib Hydrochloride<br>* Given IV<br>* Other names: MDL-107826A;Drug: Fluorouracil<br>* Given IV<br>* Other names: Timazin;Drug: Leucovorin Calcium<br>* Given IV<br>* Other names: Wellcovorin;Drug: Oxaliplatin<br>* Given IV<br>* Other names: SR-96669;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | Number of Participants with Partial Response (PR), Stable Disease (SD), Progression of Disease (POD) Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI and/or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progression of Disease (POD); POD, 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | Within 3 courses of treatment |