A Phase 2 Study of M6620 in Combination with Carboplatin compared with Docetaxel in Combination with Carboplatin in Metastatic Castration-Resistant Prostate Cancer

Protocol # :
Castration-Resistant Prostate Carcinoma
Metastatic Prostate Carcinoma
Stage IV Prostate Cancer AJCC v8
Disease Sites
Principal Investigator
Choudhury, Atish
Site Investigator
Bubley, Glenn
Site Research Nurses
Creaton, Eileen
Gundy, Kathryn, E.
Lagerstedt, Elizabeth
Leisner, Claire
Pace, Amanda
Polinski, Karen
Porter, Kathryn
Prisby, Judith
Theodore, Catherine
Walsh, Meghara

Trial Description

This phase II trial studies how well berzosertib (M6620) and carboplatin with or without
docetaxel works in treating patients with castration-resistant prostate cancer that has
spread to other places in the body (metastatic). M6620 may stop the growth of tumor cells by
blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as
carboplatin and docetaxel, work in different ways to stop the growth of tumor cells, either
by killing the cells, by stopping them from dividing, or by stopping them from spreading.
Giving M6620, carboplatin and docetaxel may work better in treating patients with metastatic
castration-resistant prostate cancer compared to carboplatin and docetaxel alone.

Eligibility Requirements

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

- 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