A Phase Ia/Ib study of talazoparib in combination with tazemetostat in metastatic castration-resistant prostate cancer (mCRPC)

Protocol # :
Metastatic Prostate Cancer
Metastatic Castration-resistant Prostate Cancer
Disease Sites
Principal Investigator
Choudhury, Atish
Site Research Nurses
Bretta, Katherine, v.
Carey, Margaret, M.
Healy, Erin, C.
Kabarame, Liliane
Leisner, Claire
Mingrino, Sage
Pace, Amanda
Prisby, Judith

Trial Description

This trial is testing whether molecularly targeted oral medications called talazoparib and
tazemetostat can be safely combined for the treatment of prostate cancer, and whether the
combination is effective in shrinking or preventing the growth of metastatic prostate cancer.

The names of the study drugs involved in this study are:

- Talazoparib

- Tazemetostat

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 for bone,
with or without PSA progression

- Patients must have metastatic disease by bone scintigraphy or other nodal or visceral
lesions on CT or MRI with a bone or soft tissue lesion amenable to image-guided
percutaneous biopsy, a castrate level of testosterone (<50ng/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 LHRH or GnRH
agonists or antagonists unless intolerant.

- Past progression on at least one novel hormonal therapy (abiraterone, enzalutamide,
apalutamide, darolutamide, galeterone, orteronel, seviteronel or equivalent) in either
the hormone-sensitive or castration-resistant disease setting.

- Not a candidate for docetaxel or cabazitaxel chemotherapy due to:

- progression within 12 months of completion or intolerance to prior taxane OR

- refusal of taxane OR

- contraindication to, or lack of fitness for taxane OR

- investigator assessment that taxane is not clinically indicated or preferred

- Age ≥18 years. Children under 18 are excluded from this study as prostate cancer is a
disease of adults

- ECOG performance status ≤1 (Karnofsky ≥70%, see Appendix A).

- Participants must have adequate organ and marrow function as defined below:

- leukocytes ≥ 3,000/mcL

- absolute neutrophil count ≥1,500/mcL

- hemoglobin ≥9 g/dL (without transfusion or growth factor in prior 28 days)

- platelets ≥ 100,000/mcL (without transfusion of growth factor in prior 28 days)

- total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN) unless known or
suspected Gilbert syndrome

- AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN

- glomerular filtration rate (GFR) ≥60 mL/min/1.73 m2 (based on Cockcroft-Gault
formula OR creatinine clearance based on 24 hour urine collection)

- Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral
therapy (with no known or predicted drug-drug interactions with talazoparib and/or
tazemetostat) with undetectable viral load within 6 months are eligible for this

- For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV
viral load must be undetectable. If suppressive therapy is indicated, there must be no
known or predicted drug-drug interactions with talazoparib and/or tazemetostat.

- Participants with a history of hepatitis C virus (HCV) infection must have been
treated and cured. For participants with HCV infection who are currently on treatment,
they are eligible if there are no known or predicted drug-drug interactions with
talazoparib and/or tazemetostat and they have an undetectable HCV viral load.

- Participants with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification. To be
eligible for this trial, participants should be class 2B or better.

- Prior treatment with a PARP inhibitor is allowed.

- Planned to undergo core biopsy of a recurrent/metastatic lesion adequate for next
generation sequencing (NGS) 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 COVID-19, this requirement
can be waived on discussion with the trial PI.

- Willing to undergo core biopsy of a recurrent/metastatic lesion adequate for next
generation sequencing (NGS) after 8 weeks (+/- 7 days) of study treatment.

- The effects of talazoparib and tazemetostat on the developing human fetus are unknown.
For this reason and because oral 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 talazoparib and tazemetostat administration.

- Ability to swallow oral medications.

- Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

- Participants who have had chemotherapy, intravenous experimental agent,
radiopharmaceutical therapy or radiotherapy within 4 weeks prior to planned cycle 1
day 1 of study treatment.

- Participants who have received oral anti-neoplastic intervention such as an oral
hormonal agent, PARP inhibitor, or oral experimental agent within 14 days prior to
planned cycle 1 day 1 of study treatment.

- Participants who have not recovered from clinically significant adverse events due to
prior anti-cancer therapy (i.e., have clinically significant residual toxicities >
Grade 1) except for stable complications of prior procedures (such as urinary
incontinence or erectile dysfunction) or Grade 2 anorexia, alopecia, neuropathy, and
fatigue, for which resolution is not required.

- Participants who are receiving any other investigational agents.

- Participants previously treated with an inhibitor of EZH2.

- 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 talazoparib or tazemetostat.

- Participants receiving the following concurrent medications:

- Participants receiving the P-gp inhibitors amiodarone, carvedilol,
clarithromycin, itraconazole, or verapamil are ineligible. Participants receiving
other P-gp inhibitors are not excluded but should be monitored for potential
increased adverse reactions.

- Participants receiving BCRP inhibitors are not excluded but should be monitored
for potential increased adverse reactions.

- Participants receiving any medications or substances that are strong or moderate
inhibitors or inducers of CYP3A4 are ineligible.

- Precaution is warranted with concomitant use of agents with a narrow therapeutic
index that are substrates of CYP3A4 and/or P-gp.

Because the lists of these agents are constantly changing, it is important to regularly
consult a frequently updated medical reference. As part of the enrollment/informed consent
procedures, the participant 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 participant is
considering a new over-the-counter medicine or herbal product.

- Participants with uncontrolled intercurrent illness including, but not limited to,
ongoing or active infection, symptomatic congestive heart failure, unstable angina
pectoris, or cardiac arrhythmia.

- Participants with 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.

- Arterial or venous thromboembolic event within the last 3 months.

- Concurrent active malignancy. Patients with non-melanomatous skin cancer, superficial
bladder cancer, cancer not needing active therapy for at least 2 years, cancer for
which the treating investigator deems the subject to be in remission, or any prior
malignancy that was treated with curative intent (no evidence of disease for at least
3 years) are also permitted to enroll.