Ovarian CancerPhase 1NCT06161493
ZEN003694 Combined With Niraparib in Patients With Metastatic or Recurrent Solid Tumors
A Phase 1 study testing ZEN003694 and Niraparib in people with Ovarian Cancer and Recurrent Solid Tumors, run by Haider Mahdi at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Ovarian Cancer, Recurrent Solid Tumors
- What is being tested?
- ZEN003694 and Niraparib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- 23 Jan 2024to 31 Dec 2029
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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.
Who cannot join
- 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)
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- 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
- Other known active cancer requiring therapy at time of study entry or that progressed or required treatment within 3 years prior to starting study drug (except for skin basal cell carcinoma or squamous cell carcinoma or in situ cervical cancer)
- Prior history with PRES
- Hypersensitivity to the active substance of to any of the excipients, including tartrazine in the capsule formulation.
- Patients with not adequately controlled hypertension despite adequate medical treatment.
- History of infection with (screening tests not required): human immunodeficiency virus; hepatitis B virus with currently active disease defined as hepatitis B surface antigen (HBsAg) positivity; or hepatitis C virus unless previously treated and viral load is undetectable except following situations:
- HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of enrollment are eligible for this trial.
- Patients with a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection are allowed to be included if: participant on a stable dose of antiviral therapy, HBV viral load below the limit of quantification. HCV viral load below the limit of quantification.
- Major surgery other than diagnostic surgery, dental surgery or stenting within 4 weeks prior to the first administration of study drug
- Concurrent participation in another clinical investigational treatment trial
- Any other reason that in the opinion of the Investigator would prevent the patient from completing participation or following the study schedule
Trial locations and contacts
1 site in 1 country.
United States1 site
UPMC Magee Womens Hospital
Pittsburgh, Pennsylvania, 15213
About this study
Official title: Phase l Study of a BET Inhibitor, ZEN003694, Combined With a PARP Inhibitor, Niraparib in Patients With Metastatic or Recurrent Solid Tumors
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.
Read the detailed description
PARPis impair the repair of single strand DNA breaks leading to double strand DNA breaks especially in patients with defects in the HR pathway. PARP is have been extensively studied in ovarian cancer and are approved for patients with germline or somatic BRCA mutant ovarian cancer after 2-3 lines of chemotherapy. PARPis have been also approved as maintenance therapy in first line and recurrent ovarian cancer after partial or complete response to platinum-based therapy. PARPis have prominent activity in BRCA mutated cancer with lower activity in the BRCA wild type HRD negative ovarian cancer. Approximately 18-24% of ovarian cancer harbor somatic or germline BRCA mutation and 50% harbor alteration in the homologous recombination (HR) pathway.
Further, PARPi therapy is frequently associated with PARPi resistance. Therefore, there is a need to reverse PARPi resistance and enhance response to PARPi in PARPi resistant ovarian cancer. Recently, significant pre-clinical evidence has shown that BETi's synergize with PARPi's through downregulation of the transcription of several HR genes. It is hypothesized that BETi may suppress HR and enhance non-homologous end joining thereby sensitizing HR-proficient cancer cells to PARP inhibition, and also BETi has been described to reverse PARPi resistance. To test this hypothesis, this Phase I trial will test the combination of niraparib and ZEN003694 in recurrent or metastatic solid cancers.
- Conditions
- Ovarian Cancer, Recurrent Solid Tumors
- Being tested
- ZEN003694, Niraparib
- Keywords
- BET inhibitor, PARP inhibitor
- Medical subject headings
- Ovarian Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ZEN003694Drug
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.
NiraparibDrug
Also called MK-4827, Zejula
An anti-cancer medication (PARP inhibitor) used for the treatment of epithelial ovarian, fallopian tube, or primary peritoneal cancer .
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: Drug: ZEN003694; Drug: Niraparib |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: Up to 12 months (study population)
Secondary outcomes (6)
Pharmacokinetics (PK)
Maximum observed concentration (Cmax) in blood taken from patients treated with ZEN003694 combined with niraparib.
Measured: Up to 30 days
Pharmacodynamics (PD)
Area under the serum concentration-time curve (AUC) in blood taken from patients treated with ZEN003694 combined with niraparib.
Measured: Up to 30 days
Objective response rate (ORR) by RECIST 1.1
Proportion of participants achieving a best response of CR or PR per RECIST v1.1, at each dose level. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Measured: Up to 6 years (study population)
Duration of Response
Time from start of treatment to disease progression or death in patients who achieve Complete Response (CR) or Partial Response (PR) (whichever is recorded first) per RECIST v1.1. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Measured: Up to 6 years (study population)
Progression-free survival (PFS)
Median number of months from start of treatment to the date of disease progression or death from any cause. Per RECISIT v1.1: Progressive Disease (PD):≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.
Measured: Up to 6 years (study population)
Overall survival (OS)
Median length of time from start of treatment that patients remain alive.
Measured: Up to 6 years (study population)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Dec 2023
- Study start23 Jan 2024
- Primary completion31 Dec 2026 (estimated)
- Study completion31 Dec 2029 (estimated)
Why it stopped: Investigator Discretion
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Ovarian CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Haider Mahdi
- Sponsor type
- University, hospital or other
- Collaborators
- GlaxoSmithKline, Zenith Epigenetics
- Responsible party
- Sponsor-investigator, Haider Mahdi, University of Pittsburgh
- Investigators
- Haider S Mahdi, MD, Principal investigator, UPMC Magee Women's Hospital, UPMC Hillman Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06161493
- Sponsor's protocol ID
- HCC 22-142
- Status last verified
- Oct 2024
- First submitted
- 27 Nov 2023
- Last updated
- 15 Oct 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 15 Oct 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase l Study of a BET Inhibitor, ZEN003694, Combined With a PARP Inhibitor, Niraparib in Patients With Metastatic or Recurrent Solid Tumors
- ClinicalTrials.gov ID
- NCT06161493
- Acronym / sponsor ID
- HCC 22-142
- Conditions
- Ovarian Cancer, Recurrent Solid Tumors
- Keywords
- BET inhibitor, PARP inhibitor
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Investigator Discretion
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Haider MahdiUniversity, hospital or other
- Collaborators
- GlaxoSmithKline, Zenith Epigenetics
- Study start
- 23 Jan 2024 (actual)
- Primary completion
- 31 Dec 2026 (estimated)
- Study completion
- 31 Dec 2029 (estimated)
- First posted
- 8 Dec 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
PARPis impair the repair of single strand DNA breaks leading to double strand DNA breaks especially in patients with defects in the HR pathway. PARP is have been extensively studied in ovarian cancer and are approved for patients with germline or somatic BRCA mutant ovarian cancer after 2-3 lines of chemotherapy. PARPis have been also approved as maintenance therapy in first line and recurrent ovarian cancer after partial or complete response to platinum-based therapy. PARPis have prominent activity in BRCA mutated cancer with lower activity in the BRCA wild type HRD negative ovarian cancer. Approximately 18-24% of ovarian cancer harbor somatic or germline BRCA mutation and 50% harbor alteration in the homologous recombination (HR) pathway.
Further, PARPi therapy is frequently associated with PARPi resistance. Therefore, there is a need to reverse PARPi resistance and enhance response to PARPi in PARPi resistant ovarian cancer. Recently, significant pre-clinical evidence has shown that BETi's synergize with PARPi's through downregulation of the transcription of several HR genes. It is hypothesized that BETi may suppress HR and enhance non-homologous end joining thereby sensitizing HR-proficient cancer cells to PARP inhibition, and also BETi has been described to reverse PARPi resistance. To test this hypothesis, this Phase I trial will test the combination of niraparib and ZEN003694 in recurrent or metastatic solid cancers.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Niraparib | Experimental | Drug: ZEN003694, Drug: NiraparibZEN003694: 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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- 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
Key exclusion criteria (25 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ZEN003694A 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. | Drug | Niraparib |
| NiraparibAlso: MK-4827, ZejulaAn anti-cancer medication (PARP inhibitor) used for the treatment of epithelial ovarian, fallopian tube, or primary peritoneal cancer . | Drug | Niraparib |
Primary outcome
Treatment-related Adverse Events (AE) and Serious Adverse Events (SAE)
Time frame: Up to 36 months (study population)
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.
Maximum Tolerated Dose (MTD) / Recommended Phase 2 Dose (RP2D)
Time frame: Up to 12 months (study population)
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.
6 secondary outcomes
Pharmacokinetics (PK)
Time frame: Up to 30 days
Pharmacodynamics (PD)
Time frame: Up to 30 days
Objective response rate (ORR) by RECIST 1.1
Time frame: Up to 6 years (study population)
Duration of Response
Time frame: Up to 6 years (study population)
Progression-free survival (PFS)
Time frame: Up to 6 years (study population)
Overall survival (OS)
Time frame: Up to 6 years (study population)
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Oct 2024.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Haider S Mahdi, MD principal investigator
UPMC Magee Women's Hospital, UPMC Hillman Cancer Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing ZEN003694 and Niraparib in people with Ovarian Cancer and Recurrent Solid Tumors, run by Haider Mahdi at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 15 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Treatment-related Adverse Events (AE) and Serious Adverse Events (SAE) (time frame: Up to 36 months (study population)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Oct 2024.