Evaluating Safety & Efficacy Belinostat Combo w Nivo Alone & w Ipi in Patients w Treated Metastatic/Advanced Carcinomas w ARID1A Lof Mutation

NCT04315155 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: HCI130490
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This is an open-label Phase I trial designed to determine the phase 2 recommended dose (RP2D) of belinostat in combination with nivolumab with or without ipilimumab.

Conditions

Metastatic Adenocarcinoma

Outcome Measures

Primary Outcomes (2)

• rate of dose limiting toxicities (DLTs) during defined DLT period

  assess the recommended phase 2 dose of belinostat in combination with nivolumab in patients with advanced solid tumors harboring ARID1A mutations.

  9-12 months

• rate of intolerable refractory immune mediated adverse events assessed during the defined DLT evaluation period

  assess the safety and tolerability of belinostat in combination with nivolumab with and without ipilimumab in patients with advanced solid tumors.

  12-18 months

Secondary Outcomes (6)

• frequency and characterization of Adverse Events (AE)

  up to 5 years

• • The rate of clinical benefit defined as the proportion of evaluable patients achieving stable disease, a partial response, or a complete response per RECIST 1.1 criteria

  up to 5 years

• • Objective response rate (ORR) as defined as the proportion of evaluable patients achieving a partial response or a complete response per RECIST 1.1 criteria.

  up to 5 years

• • Duration of response (DoR) as defined as the time from documented tumor response to disease progression as defined by RECIST 1.1.

  up to 5 years

• • Progression-free survival (PFS) as defined as the time from the initiation of study therapy to disease progression per RECIST 1.1, initiation of alternative therapy, or death from any cause.

  up to 5 years

Study Arms (2)

Double Regimen

EXPERIMENTAL

belinostat in combination with nivolumab

Drug: Belinostat; Drug: nivolumab

Triplet Regimen

EXPERIMENTAL

belinostat in combination with nivolumab and ipilimumab

Drug: ipilimumab; Drug: nivolumab; Drug: Belinostat

Interventions

Belinostat DRUG

Doublet Regimen Dose levels for Part 1: Belinostat Dose Level 1 (starting dose) 500 mg/m2 Dose Level 2 750 mg/m2 Dose Level 3 1000 mg/m2

Double Regimen

nivolumab DRUG

Doublet Regimen Dose levels for Part 1 Nivolumab Dose Level 1 (starting dose) 360 mg Dose Level 2 360 mg Dose Level 3 360 mg

Double Regimen

ipilimumab DRUG

Triplet and Doublet Regimen Dose Levels for Phase 2 Ipilimumab Doublet Dose n/a Triplet Dose 1 mg/kg

Triplet Regimen

Eligibility Criteria

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

You may qualify if:

• Male or female subject aged ≥ 18 years.
• Histologically confirmed solid tumor with metastatic disease or with unresectable, locally advanced disease
• Patients must have progressed on at least one prior therapy; and
• Have no further standard of care options or the available options are associated with minimal overall survival benefit; or
• Have no further clinically acceptable therapy; or
• The patient has declined standard therapy.
• The discussion regarding the choice of standard therapy offered, if available, and patient's choice and reason(s) to decline standard therapy should be documented clearly in the research chart.
• Patients may have progressed on immune checkpoint inhibitor therapy.
• Part 1 and Part 2, Cohorts 1 and 2: Malignancy harboring ARID1A loss of function (lof) mutations as determined by the standard of care next-generation sequencing. The advanced solid tumors enrolled are anticipated to be, but not restricted to, urothelial carcinoma, gastrointestinal malignancies (gastric, colorectal, pancreatic), and gynecological malignancies (ovarian and endometrial).
• Part 2, Cohort 3: Malignancy without ARID1A loss of function (lof) mutation (ARID1A wild type).
• Subject must have measurable disease by RECIST 1.1 criteria by CT or MRI.
• ECOG Performance Status ≤ 2.
• Adequate organ function as defined as:
• Hematologic:
• Absolute neutrophil count (ANC) ≥ 1500/mm3

You may not qualify if:

• Homozygous for UGT1A1\*28 allele or Gilbert syndrome.
• Subject has received systemic antineoplastic therapy (including unconjugated therapeutic antibodies and toxin immunoconjugates) or any investigational therapy ≤ 14 days or within 5 half-lives before starting study treatment, whichever is shorter.
• Subject has received radiotherapy ≤ 14 days before the first dose of study treatment. Localized radiation therapy for the treatment of symptomatic bone metastasis is allowed during that timeframe.
• Subjects who have undergone major surgery ≤ 3 weeks before starting study drug or who have not fully recovered from major surgery.
• Diagnosis of any other malignancy within 2 years before study enrollment, except for adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the breast, bladder or of the cervix, and low-grade (Gleason 6 or below) prostate cancer on surveillance with no plans for treatment intervention (eg, surgery, radiation, or castration) or prostate cancer that has been adequately treated with prostatectomy or radiotherapy and currently with no evidence of disease or symptoms is allowed.
• Known brain metastases or cranial epidural disease.
• Note: Brain metastases or cranial epidural disease adequately treated with radiotherapy and/or surgery and stable for at least 4 weeks before the first dose of study treatment will be allowed on trial. Subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of the first dose of study treatment.
• Current evidence of uncontrolled, clinically significant intercurrent illness including, but not limited to, the following conditions:
• Cardiovascular disorders:
• Congestive heart failure New York Heart Association Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias.
• Stroke (including transient ischemic attack \[TIA\]), myocardial infarction (MI), or other ischemic events, or thromboembolic event (eg, deep venous thrombosis, pulmonary embolism) within 3 months before the first dose.
• Uncontrolled hypertension defined as a sustained systolic blood pressure ≥ 160mmHg or a diastolic blood pressure ≥ 100mmHg despite optimal management.
• Note: Patients with uncontrolled hypertension who are not optimally managed may be rescreened once controlled hypertension is achieved.
• Patients with uncorrectable prolonged QTc (Bezet formula) \> 480 msec or concomitant use of medications(s) with a known risk of inducing Torsade de Pointes if such treatment cannot be discontinued or switched to a different medication before starting the study drug.
• Note: If a single ECG shows a QTc with an absolute value \> 480 msec, two additional ECGs approximately 2 minutes apart must be performed within 30 minutes of the initial ECG, and the average of these three consecutive results for QTc will be used.

Sponsors & Collaborators

• University of Utah: lead
• Bristol-Myers Squibb: collaborator
• Acrotech Biopharma Inc.: collaborator

MeSH Terms

Conditions

Adenocarcinoma

Interventions

belinostat; Nivolumab; Ipilimumab

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is an open-label Phase I trial designed to determine the phase 2 recommended dose (RP2D) of belinostat in combination with nivolumab with or without ipilimumab. Overall, the trial will assess dosing and safety of two regimens in the study population: * The double regimen: belinostat in combination with nivolumab; * The triplet regimen: belinostat in combination with nivolumab and ipilimumab.

Study Record Dates

• First Submitted: March 17, 2020
• First Posted: March 19, 2020
• Study Start: October 1, 2020
• Primary Completion: September 1, 2023
• Study Completion: September 1, 2025
• Last Updated: October 28, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will not share