ZEN003694 Combined With Niraparib in Patients With Metastatic or Recurrent Solid Tumors

NCT06161493 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: HCC 22-142
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

This Phase I, open label, dose determining study of oral niraparib in combination with ZEN003694 given daily in 28-day cycles will enroll patients with metastatic or recurrent solid cancer. Dose escalation will follow the mTPI-2/Keyboard design. Eligible patients will receive therapy until disease progression or unacceptable toxicities are experienced.

Conditions

Ovarian Cancer; Recurrent Solid Tumors

Keywords

BET inhibitor; PARP inhibitor

Outcome Measures

Primary Outcomes (2)

• Treatment-related Adverse Events (AE) and Serious Adverse Events (SAE)

  Frequency and severity of adverse events (AE) per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0. The maximum grade for each toxicity type will be recorded for each patient.

  Up to 36 months (study population)

• Maximum Tolerated Dose (MTD) / Recommended Phase 2 Dose (RP2D)

  Frequency of dose-limiting toxicities (DLTs) (AEs leading to discontinuation of treatment). The mTPI-2/Keyboard design is a Bayesian interval dose determining design. The target toxicity rate for the MTD for this combination therapy is defined at 0.30 with an acceptable toxicity probability interval (0.25, 0.35). The MTD is selected based on the dose estimate closest to the target toxicity rate, and the recommend phase II dose will be determined based on the MTD and all available safety and PK data.

  Up to 12 months (study population)

Secondary Outcomes (6)

• Pharmacokinetics (PK)

  Up to 30 days

• Pharmacodynamics (PD)

  Up to 30 days

• Objective response rate (ORR) by RECIST 1.1

  Up to 6 years (study population)

• Duration of Response

  Up to 6 years (study population)

• Progression-free survival (PFS)

  Up to 6 years (study population)

Study Arms (1)

Niraparib

EXPERIMENTAL

ZEN003694: Oral capsules - Starting dose 36 mg Dose escalated to 48 mg, following the mTPI-2/Keyboard design administered orally once daily in 28-day cycles Niraparib: Oral tablets - Starting dose 100 mg Dose escalated to 200 mg, following the mTPI-2/Keyboard design administered once daily at the same time as ZEN003694

Drug: ZEN003694; Drug: Niraparib

Interventions

ZEN003694 DRUG

A bromodomain extra-terminal inhibitor (BETi) that blocks a group of proteins called bromodomain and extra-terminal (BET), which may counteract the effect of NSD3 on tumor growth.

Niraparib

Niraparib DRUG

An anti-cancer medication (PARP inhibitor) used for the treatment of epithelial ovarian, fallopian tube, or primary peritoneal cancer .

Also known as: MK-4827, Zejula

Niraparib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Eastern Cooperative Oncology Group (ECOG) status 0 or 1
• Pathologically documented recurrent or metastatic solid tumor who progressed on standard of care therapy or for whom standard of care does not exist.
• Prior PARPi therapy is allowed
• Have had no more than 5 prior cancer therapy treatment regimens, of which a maximum of 4 were cytotoxic chemotherapy or DNA-damaging agents like PARPi-containing regimens
• Measurable disease per RECIST 1.1
• Known BRCA1/2 status or willing to be tested
• Adequate laboratory parameters at Screening
• Treated females patients not breastfeeding, pregnant or of childbearing potential, or permanently sterile or who are post-menopausal (no menses for at least 1 year without an alternative medical cause and FSH levels in the post-menopausal range)
• Ability to swallow capsules and comply with study procedures
• Ability to sign informed consent form prior to initiation of any study procedures.
• Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study enrollment, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable with evidence of no disease progression for 6 months.

You may not qualify if:

• Current or anticipated use of medications known to be strong inhibitors or inducers of CYP3A4 or substrates of CYP1A2 with narrow therapeutic windows. Strong inhibitors, inducers or substrates must be discontinued at least 7 days prior to the first administration of study drug.
• Current or anticipated use within 7 days prior to the first administration of study drug, or during the study, of strong P-gp inhibitors.
• Use of oral Factor Xa inhibitors (i.e., rivaroxaban, apixaban, betrixaban, edoxaban otamixaban, letaxaban, eribaxaban) and Factor IIa inhibitors (i.e., dabigatran). Low molecular weight heparin is allowed
• Radiation to \>25% of the bone marrow
• Treatment with a bone-targeted radionuclide within 6 weeks of first dose of study drug
• Have previously received an investigational BET inhibitor (including previous participation in studies with Zenith drug, ZEN003694)
• QTcF interval \> 470 msec
• Insufficient recovery from prior treatment-related toxicities except for alopecia, fatigue and Grade 2 neuropathy
• Non-healing wound, ulcer or bone fracture (not including a pathological bone fracture caused by a pre-existing pathological bone lesion)
• Brain metastases not adequately treated and/or clinically stable (at the discretion of the Investigator) for at least 6 months prior to the start of study treatment.
• Known impaired cardiac function or clinically significant cardiac disease such as uncontrolled supraventricular arrhythmia, ventricular arrhythmia requiring therapy, or congestive heart failure (New York Heart Association functional class III or IV)
• Myocardial infarction or unstable angina within 6 months prior to the first administration of study drug
• Known myelodysplastic syndrome
• Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy, or any other condition that could compromise safety or the patient's participation in the study
• Impairment of gastrointestinal function that may significantly alter the absorption of ZEN003694 or niraparib

Sponsors & Collaborators

• Haider Mahdi: lead
• GlaxoSmithKline: collaborator
• Zenith Epigenetics: collaborator

Study Sites (1)

UPMC Magee Womens Hospital

Pittsburgh, Pennsylvania, 15213, United States

Location

MeSH Terms

Conditions

Ovarian Neoplasms

Interventions

niraparib

Condition Hierarchy (Ancestors)

Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders

Study Officials

• Haider S Mahdi, MD

  UPMC Magee Women's Hospital, UPMC Hillman Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor of Medicine

Study Record Dates

• First Submitted: November 27, 2023
• First Posted: December 8, 2023
• Study Start: January 23, 2024
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2029
• Last Updated: October 15, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)