M6620 and Carboplatin With or Without Docetaxel in Treating Patients With Metastatic Castration-Resistant Prostate Cancer
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| ClinicalTrials.gov Identifier: NCT03517969 |
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Recruitment Status :
Active, not recruiting
First Posted : May 8, 2018
Last Update Posted : January 2, 2024
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Castration-Resistant Prostate Carcinoma Metastatic Prostate Carcinoma Stage IV Prostate Cancer AJCC v8 | Drug: Berzosertib Drug: Carboplatin Drug: Docetaxel Other: Laboratory Biomarker Analysis | Phase 2 |
PRIMARY OBJECTIVE:
I. To assess the difference in response rate (either achievement of prostate specific antigen [PSA] reduction of greater than 50% or radiographic response by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) of the combination of berzosertib (M6620) (VX-970, berzosertib) and carboplatin as compared to the combination of docetaxel and carboplatin.
SECONDARY OBJECTIVES:
I. To assess the difference in time to PSA progression by Prostate Cancer Working Group (PCWG)2 criteria of the combination of M6620 (VX-970, berzosertib) and carboplatin as compared to the combination of docetaxel and carboplatin.
II. To describe radiographic progression-free survival and progression-free survival by PCWG3 criteria in both arms of the study.
III. Assess the relationship with homologous recombination deficiency (HRD) detected from baseline tumor biopsy with response to the combination of M6620 (VX-970, berzosertib) and carboplatin and the combination of docetaxel and carboplatin.
IV. To describe the safety and adverse events from the combination of M6620 (VX-970, berzosertib) + carboplatin as well the combination of docetaxel + carboplatin.
EXPLORATORY OBJECTIVES:
I. Comparison of overall survival in the two arms of the study. II. Explore response rate, time to PSA progression, radiographic progression-free survival, and progression-free survival by PCWG3 criteria in patients who initially receive docetaxel + carboplatin after crossover to M6620 + carboplatin.
III. To assess the relationship with homologous recombination deficiency (HRD) detected from baseline circulating free deoxyribonucleic acid (DNA) (cfDNA) with response to the combination of M6620 and carboplatin and the combination of docetaxel and carboplatin, and describe alterations seen in cfDNA (and optional tumor biopsy) at end of study.
OUTLINE: Patients are randomized to 1 of 2 groups.
ARM A (docetaxel, carboplatin): Patients receive docetaxel intravenously (IV) over 60 minutes and carboplatin IV over 30 minutes on day 1 or carboplatin alone on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients have PSA progression or radiographic progression may crossover to Arm B.
ARM B (carboplatin, berzosertib): Patients receive carboplatin IV over 30 minutes on day 1 and berzosertib IV over 60-90 minutes on days 2 and 9. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up between 30-42 days.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 130 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | A Phase 2 Study of M6620 (VX-970, Berzosertib) in Combination With Carboplatin Compared With Docetaxel in Combination With Carboplatin in Metastatic Castration-Resistant Prostate Cancer |
| Actual Study Start Date : | May 29, 2019 |
| Estimated Primary Completion Date : | December 31, 2024 |
| Estimated Study Completion Date : | December 31, 2024 |
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: Arm A (docetaxel, carboplatin)
Patients receive docetaxel IV over 60 minutes and carboplatin IV over 30 minutes, or carboplatin alone on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients who have PSA progression or radiographic progression may crossover to Arm B.
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Drug: Carboplatin
Given IV
Other Names:
Drug: Docetaxel Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies |
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Experimental: Arm B (carboplatin, berzosertib)
Patients receive carboplatin IV over 30 minutes on day 1 and berzosertib IV over 60-90 minutes on days 2 and 9. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
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Drug: Berzosertib
Given IV
Other Names:
Drug: Carboplatin Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies |
- Response rate (complete response + partial response) [ Time Frame: Up to 2 years ]Defined by radiographic response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or prostate specific antigen [PSA] response of > 50%). Will be conducted using the Cochran-Mantel-Haenszel test, with one-sided p-value of =< 0.05 considered significant.
- Progression-free survival (PFS) [ Time Frame: From the time of randomization up to 2 years ]Assessed by Prostate Cancer Working Group (PCWG)3. PFS to be estimated with the Kaplan Meier methodology. Median and event-free rate at selected time points will be provided with 95% confidence interval.
- Time to PSA progression [ Time Frame: From the time of randomization up to 2 years ]Assessed by PCWG2. PSA progression will be estimated with the Kaplan Meier methodology. Median and event-free rate at selected time points will be provided with 95% confidence interval. Comparison of time to PSA progression between arms will be conducted using the log-rank test.
- Radiographic progression-free survival (rPFS) [ Time Frame: From the time of randomization up to 2 years ]Assessed by RECIST 1.1. rPFS will be estimated with the Kaplan Meier methodology. Median and event-free rate at selected time points will be provided with 95% confidence interval.
- Incidence of adverse events [ Time Frame: Up to 2 years ]Will be summarized according to treatment arm. For toxicity reporting, all adverse events will be graded and analyzed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Type of adverse events, intensity (grading), and attribution will be provided in a listing. All adverse events resulting in discontinuation, dose modification, and/or dosing interruption, and/or treatment delay of drug will also be summarized. Laboratory test results will be classified according to the CTCAE version 5.0.
- Overall survival (OS) [ Time Frame: From the time of randomization up to 2 years ]OS will be estimated with the Kaplan Meier methodology. Comparison of OS between arms will be conducted using the log-rank test base on the intention-to-treat approach, where two treatment arms will be compared regardless of cross-over or any subsequent therapy.
- Gene mutation frequencies [ Time Frame: Baseline up to 2 years ]Gene mutation frequencies and mean +/- standard deviation of quantitative biomarkers will be summarized by arm and in overall population at baseline and/or at end of study.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | Male |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
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Participants must have histologically or cytologically confirmed prostate cancer (code 10036910) with progressive disease at the time of study entry by either
- Sequence of at least 2 rising PSA values at a minimum of 1-week intervals
- Radiographic progression per RECIST1.1 for soft tissue and/or per PCWG3^2 for bone, with or without PSA progression
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Patients must have metastatic disease by bone scan or other nodal or visceral lesions on computed tomography (CT) or magnetic resonance imaging (MRI) and a castrate level of testosterone (< 50 ng/dL) and evaluable for disease response by either
- Baseline PSA >= 2.0 ng/mL OR
- Measurable disease per RECIST 1.1
- NOTE: Subjects must maintain a castrate state; if they have not had an orchiectomy, they must continue to receive luteinizing hormone-releasing hormone (LHRH) or gonadotropin-releasing hormone (GnRH) agonists or antagonists unless intolerant
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At least 2 prior treatments for castration resistant prostate cancer as follows:
- Past progression or intolerance to at least one secondary hormonal therapy (abiraterone, enzalutamide, galeterone, apalutamide, darolutamide, orteronel, seviteronel or equivalent)
- Past progression or intolerance to taxane-based chemotherapy
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
- Leukocytes >= 3,000/mcL
- Absolute neutrophil count >= 1,500/mcL
- Hemoglobin >= 9 g/dL (transfusion permitted)
- Platelets >= 150,000/mcL (without transfusion or growth factor in prior 28 days)
- Total bilirubin =< 1.5 x institutional upper limit of normal, unless the subject has known or suspected Gilbert's syndrome
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal or =< 5 x if presence of liver metastases
- Creatinine clearance >= 40 mL/min/1.73 m^2
- Prior treatment with mTOR inhibitors, cytostatic tyrosine kinase inhibitor (TKI), or biologic therapies allowed
- Prior treatment with PARP inhibitors permitted
- Patients with allergy or intolerance to docetaxel, grade 2 neuropathy are allowed on study, but if randomized to Arm A will receive carboplatin as a single agent (area under curve [AUC] 5) rather than docetaxel+carboplatin; they must be fit for carboplatin chemotherapy as determined by the treating investigator
- Presence of a lesion (bone or soft tissue) amenable to image-guided percutaneous biopsy adequate for next generation sequencing (NGS), and planned to undergo core biopsy after trial registration but prior to cycle 1 day 1 of therapy; confirmation of adequacy of this biopsy material for NGS is NOT required for initiation of therapy; if elective biopsies are not being performed at the treating institution due to preparations or precautions related to coronavirus disease 2019 (COVID-19), this requirement can be waived on discussion with the trial principal investigator (PI)
- The effects of M6620 (VX-970, berzosertib), carboplatin and docetaxel on the developing human fetus are unknown. For this reason and because DNA-damage response inhibitors and chemotherapeutic agents are known to be teratogenic, men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of carboplatin and M6620 (VX-970, berzosertib) administration
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to planned cycle 1 day 1 of study treatment; patients on an oral anti-neoplastic such as an oral hormonal agent, PARP inhibitor or oral experimental agent should discontinue >= 14 days prior to planned cycle 1 day 1 of study treatment
- Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1), except for grade 2 anorexia, alopecia, neuropathy, and fatigue, for which resolution is not required
- Patients who are receiving any other investigational agents
- Patients with known brain metastases or leptomeningeal disease should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to M6620 (VX-970, berzosertib) or carboplatin; (patients with allergy to docetaxel will be allowed on study, but docetaxel will be excluded from their treatment regimen)
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Subjects receiving treatment with ototoxic or nephrotoxic medications that cannot be discontinued at least 7 days before first dose of carboplatin and for the duration of the study; inadvertent or short-term use on study will not cause a subject to be ineligible; if a short course of therapy with nephrotoxic or ototoxic medication is anticipated and required, carboplatin should be discontinued until 7 days after this course is completed; patients on continuous medications that are potentially nephrotoxic who have had no evidence of nephrotoxicity from these medications at study entry are allowed to continue those medicines on trial
- M6620 (VX-970, berzosertib) is primarily metabolized by CYP3A4; therefore, concomitant administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir and saquinavir) or inducers of CYP3A4 (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, St. John's Wort) is prohibited; because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference for a list of drugs to avoid or minimize use of; Patient Drug Information Handout and Wallet Card should be provided to patients; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- Pregnant and nursing women are excluded from this study because they do not develop prostate cancer
- Human immunodeficiency (HIV)-positive participants with detectable viral load and/or CD4 count =< 300 are ineligible due to increased risk of lethal infections when treated with marrow-suppressive therapy; HIV-positive patients with undetectable viral loads and CD4 counts > 300, and not on interacting antiretroviral therapy may be eligible after discussing with the principal investigator
- Prior treatment with platinum-containing regimen or ATR inhibitor for prostate cancer
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03517969
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| Principal Investigator: | Atish D Choudhury | Dana-Farber - Harvard Cancer Center LAO |
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT03517969 |
| Other Study ID Numbers: |
NCI-2018-00790 NCI-2018-00790 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) 10191 ( Other Identifier: Dana-Farber - Harvard Cancer Center LAO ) 10191 ( Other Identifier: CTEP ) UM1CA186709 ( U.S. NIH Grant/Contract ) |
| First Posted: | May 8, 2018 Key Record Dates |
| Last Update Posted: | January 2, 2024 |
| Last Verified: | December 2023 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Carcinoma Prostatic Neoplasms Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Genital Neoplasms, Male Urogenital Neoplasms Neoplasms by Site Genital Diseases, Male Genital Diseases |
Urogenital Diseases Prostatic Diseases Male Urogenital Diseases Carboplatin Docetaxel Antineoplastic Agents Tubulin Modulators Antimitotic Agents Mitosis Modulators Molecular Mechanisms of Pharmacological Action |