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.
Inclusion Criteria:
- 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
- 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
- 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)
- 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
