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

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

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.

Study Overview

• Status: Completed
• Conditions: Stage IV Ovarian Germ Cell Tumor; Recurrent Ovarian Germ Cell Tumor; Stage III Testicular Cancer; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Extragonadal Seminoma; Recurrent Malignant Extragonadal Germ Cell Tumor; Recurrent Malignant Extragonadal Non-Seminomatous Germ Cell Tumor; Stage IV Extragonadal Non-Seminomatous Germ Cell Tumor; Stage IV Extragonadal Seminoma
• Intervention / Treatment: Drug: Fluorouracil; Drug: Oxaliplatin; Drug: Leucovorin Calcium; Drug: Alvocidib Hydrochloride

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Beverly Hills, California, United States, 90211-1850
      • Tower Cancer Research Foundation
    • Duarte, California, United States, 91010
      • City of Hope Comprehensive Cancer Center
    • Los Angeles, California, United States, 90033
      • USC / Norris Comprehensive Cancer Center
    • Sacramento, California, United States, 95817
      • University of California Davis Comprehensive Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Cancer Institute (UPCI)
    • Pittsburgh, Pennsylvania, United States, 15213
      • UPMC-Presbyterian Hospital
  • Wisconsin
    • Wisconsin Rapids, Wisconsin, United States, 54494
      • Riverview Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A (alvocidib and oxaliplatin); 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: Oxaliplatin; Given IV; Other Names: 1-OHP; Dacotin; Dacplat; Eloxatin; Diaminocyclohexane Oxalatoplatinum; Eloxatine; JM-83; Oxalatoplatin; Oxalatoplatinum; RP 54780; RP-54780; SR-96669; Drug: Alvocidib Hydrochloride; Given IV; Other Names: HMR 1275; L-868275; 4H-1-Benzopyran-4-one, 2-(2-chlorophenyl)-5, 7-dihydroxy-8-(3-hydroxy-1-methyl-4-piperidinyl)-, hydrochloride, (-)-cis-; Flavopiridol Hydrochloride; HL-275; L-86-8275; MDL 107,826A; MDL-107826A
Experimental: 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.	Drug: Fluorouracil; Given IV; Other Names: 5-FU; 5-Fluracil; Fluracil; 5-Fluoro-2,4(1H, 3H)-pyrimidinedione; 5-Fluorouracil; AccuSite; Fluoro Uracil; Fluouracil; Flurablastin; Fluracedyl; Fluril; Fluroblastin; Ribofluor; Ro 2-9757; Ro-2-9757; Adrucil; Efudex; Actino-Hermal; Arumel; Cytosafe; Efurix; Fiverocil; Fluoroplex; Flurox; Timazin; Drug: Oxaliplatin; Given IV; Other Names: 1-OHP; Dacotin; Dacplat; Eloxatin; Diaminocyclohexane Oxalatoplatinum; Eloxatine; JM-83; Oxalatoplatin; Oxalatoplatinum; RP 54780; RP-54780; SR-96669; Drug: Leucovorin Calcium; Given IV; Other Names: Wellcovorin; folinic acid; Adinepar; Calcifolin; Calcium (6S)-Folinate; Calcium Folinate; Calcium Leucovorin; Calfolex; Calinat; Cehafolin; Citofolin; Citrec; Citrovorum Factor; Cromatonbic Folinico; Dalisol; Disintox; Divical; Ecofol; Emovis; Factor, Citrovorum; Flynoken A; Folaren; Folaxin; FOLI-cell; Foliben; Folidan; Folidar; Folinac; Folinate Calcium; Folinic Acid Calcium Salt Pentahydrate; Folinoral; Folinvit; Foliplus; Folix; Imo; Lederfolat; Lederfolin; Leucosar; leucovorin; Rescufolin; Rescuvolin; Tonofolin; Drug: Alvocidib Hydrochloride; Given IV; Other Names: HMR 1275; L-868275; 4H-1-Benzopyran-4-one, 2-(2-chlorophenyl)-5, 7-dihydroxy-8-(3-hydroxy-1-methyl-4-piperidinyl)-, hydrochloride, (-)-cis-; Flavopiridol Hydrochloride; HL-275; L-86-8275; MDL 107,826A; MDL-107826A

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity	graded using the NCI CTCAE version 4.0.See adverse event section	Up to 4 years
Progression-free Survival		From treatment start until first documented progression or death, assessed up to 4 years
Time to Tumor Response		From treatment start until first documented CR or PR, assessed up to 4 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Darren Feldman, Memorial Sloan Kettering Cancer Center

Study record dates

Study Major Dates

• Study Start: June 1, 2009
• Primary Completion (Actual): August 1, 2014
• Study Completion (Actual): August 1, 2014

Study Registration Dates

• First Submitted: August 12, 2009
• First Submitted That Met QC Criteria: August 12, 2009
• First Posted (Estimate): August 13, 2009

Study Record Updates

• Last Update Posted (Actual): March 10, 2017
• Last Update Submitted That Met QC Criteria: January 20, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Female; Endocrine System Diseases; Disease Attributes; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Genital Neoplasms, Male; Testicular Diseases; Neoplasms; Neoplasms, Germ Cell and Embryonal; Testicular Neoplasms; Recurrence; Ovarian Neoplasms; Seminoma; Germinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Growth Substances; Growth Inhibitors; Micronutrients; Protein Kinase Inhibitors; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Antidotes; Vitamin B Complex; Hematinics; Fluorouracil; Oxaliplatin; Leucovorin; Calcium; Levoleucovorin; Folic Acid; Calcium, Dietary; Alvocidib
• Other Study ID Numbers: NCI-2011-01405 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U01CA069912 (U.S. NIH Grant/Contract); U01CA099168 (U.S. NIH Grant/Contract); U01CA062505 (U.S. NIH Grant/Contract); U01CA069856 (U.S. NIH Grant/Contract); P30CA008748 (U.S. NIH Grant/Contract); U01CA062491 (U.S. NIH Grant/Contract); N01CM00071 (U.S. NIH Grant/Contract); N01CM62206 (U.S. NIH Grant/Contract); MSKCC-09034; CDR0000646950; 09-034 (Memorial Sloan-Kettering Cancer Center); 8258 (Other Identifier: CTEP)