Phase Ia/Ib Talazoparib + Tazemetostat for mCRPC

  • STATUS
    Recruiting
  • End date
    Sep 30, 2023
  • participants needed
    38
  • sponsor
    Dana-Farber Cancer Institute
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Updated on 4 October 2022
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Summary

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

Description

This is a Phase 1a/1b clinical trial to assess safety, tolerability and preliminary clinical activity of the combination of talazoparib with tazemetostat in metastatic castration-resistant prostate cancer (mCRPC) patients.

The U.S. Food and Drug Administration (FDA) has not approved talazoparib or tazemetostat for metastatic castration-resistant prostate cancer (mCRPC) but they have been approved for other uses. Talazoparib has been approved for use in breast cancer, and tazemetostat has been approved for use in certain types of sarcoma and lymphoma.

Talazoparib is an orally administered molecularly targeted chemotherapy drug called a "PARP inhibitor", which acts to block the ability of cancer cells to repair certain forms of damage to their DNA - the accumulation of damaged DNA causes certain cancer cells to die. Other PARP inhibitors are already approved for use in prostate cancer patients with specific gene mutations detected in their blood or in their cancer, and talazoparib is currently being studied for treatment of prostate cancer in other clinical trials.

Tazemetostat is an orally administered molecularly targeted chemotherapy drug called an "EZH2 inhibitor", which acts to block the production of proteins encoded by DNA in the cancer cells that are important in cancer growth and survival. Tazemetostat is also being studied for the treatment of prostate cancer in other clinical trials. In the laboratory setting, tazemetostat causes changes in protein levels in prostate cancer cells that make them sensitive to dying in the presence of PARP inhibitors.

The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits.

The study design involves two parts. The first part is called the "dose escalation" to find a safe dose for the combination of talazoparib and tazemetostat. The second part is called the "dose expansion" where additional participants are treated at the safe dose identified in the first part of the study.

Participants will receive study treatment for as long as they do not have serious side effects and their disease does not get worse. Participants will be followed after completion of study treatment for up to 24 months.

It is expected that about 38 people will take part in this research study.

Funding for this research is provided by a grant awarded by the non-profit Prostate Cancer Foundation along with Pfizer, Inc. In addition, Pfizer is supporting the study by providing the study drug talazoparib. Epizyme, Inc. is supporting the study by providing the study drug tazemetostat.

Details
Condition Metastatic Prostate Cancer, Metastatic Castration-resistant Prostate Cancer
Treatment Tazemetostat, Talazoparib
Clinical Study IdentifierNCT04846478
SponsorDana-Farber Cancer Institute
Last Modified on4 October 2022

Eligibility

 Yes No Not Sure

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-
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
guided percutaneous biopsy, a castrate level of testosterone (<50ng/dL), and
evaluable for disease response by either
Not a candidate for docetaxel or cabazitaxel chemotherapy due to
Baseline PSA ≥ 2.0 ng/mL OR
progression within 12 months of completion or intolerance to prior taxane OR
refusal of taxane OR
Past progression on at least one novel hormonal therapy (abiraterone, enzalutamide
apalutamide, darolutamide, galeterone, orteronel, seviteronel or equivalent)
contraindication to, or lack of fitness for taxane OR
investigator assessment that taxane is not clinically indicated or preferred
in either the hormone-sensitive or castration-resistant disease setting
Participants must have adequate organ and marrow function as defined below
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)
leukocytes ≥ 3,000/mcL
absolute neutrophil count ≥1,500/mcL
hemoglobin ≥9 g/dL (without transfusion or growth factor in prior 28 days)
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
platelets ≥ 100,000/mcL (without transfusion of growth factor in prior 28 days)
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
total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN) unless known or suspected Gilbert syndrome
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
AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN
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
glomerular filtration rate (GFR) ≥60 mL/min/1.73 m2 (based on Cockcroft-Gault formula OR creatinine clearance based on 24 hour urine collection)
Willing to undergo core biopsy of a recurrent/metastatic lesion adequate for next generation sequencing (NGS) after 8 weeks (+/- 7 days) of study treatment
Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral
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
therapy (with no known or predicted drug-drug interactions with talazoparib
Ability to swallow oral medications
and/or tazemetostat) with undetectable viral load within 6 months are eligible
for this trial
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
Arterial or venous thromboembolic event within the last 3 months
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
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
years) are also permitted to enroll
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