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Ribociclib&Belinostat In Patients w Metastatic Triple Neg Breast Cancer & Recurrent Ovarian Cancer w Response Prediction By Genomics (CHARGE)

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ClinicalTrials.gov Identifier: NCT04315233
Recruitment Status : Recruiting
First Posted : March 19, 2020
Last Update Posted : November 10, 2020
Sponsor:
Collaborators:
Novartis
Acrotech Biopharma
Information provided by (Responsible Party):
University of Utah

Brief Summary:
This is an open-label, multi-center, phase I study designed to assess the maximum tolerated dose of ribociclib and belinostat in combination. The trial will open with a dose escalation followed by an expansion cohort at the identified dose. Dose escalation will be open to the enrollment of patients diagnosed with triple-negative breast cancer or ovarian cancer. Dose expansion will only be open to patients diagnosed with triple-negative breast cancer.

Condition or disease Intervention/treatment Phase
Metastatic Breast Cancer Recurrent Ovarian Carcinoma Drug: Ribociclib Drug: Belinostat Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 34 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: modified 3+3 dose escalation followed by an expansion cohort at the identified Recommended Phase 2 Dose (RP2D). Dose escalation will be open to the enrollment of patients diagnosed with triple-negative breast cancer or ovarian cancer. However, dose expansion will only be open to the enrollment of patients diagnosed with triple-negative breast cancer
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/Ib Trial of the CDK4/6 Antagonist Ribociclib And The HDAC Inhibitor Belinostat In Patients With Metastatic Triple Negative Breast Cancer And Recurrent Ovarian Cancer With Response Prediction By Genomics (CHARGE)
Actual Study Start Date : October 29, 2020
Estimated Primary Completion Date : August 2023
Estimated Study Completion Date : August 2025


Arm Intervention/treatment
Experimental: Treatment: all patients
Ribociclib and belinostat will be given at escalating doses and on multiple administration schedules throughout the dose escalation component of the study. The MTD identified in the dose escalation component will be used to define the dose and administration schedule used in the dose expansion.
Drug: Ribociclib
Ribociclib Dose Level 0 (starting dose) 200mg QD Dose Level 1A 400mg on Days 8-28 Dose Level 1B 200mg QD Dose Level 2 400mg on Days 8-28

Drug: Belinostat
Belinostat Dose Level 0 (starting dose) 600mg/m2 on Days 1-5 Dose Level 1A 600mg/m2 on Days 1-5 Dose Level 1B 1000mg/m2 on Days 1-5 Dose Level 2 1000mg/m2 on Days 1-5




Primary Outcome Measures :
  1. MTD of ribociclib and belinostat combination [ Time Frame: C1D1 to C2D1 (each cycle is 28 days) ]
    incidence of DLTs during the defined DLT period


Secondary Outcome Measures :
  1. frequency and characterization of AEs and SAEs [ Time Frame: 36 months ]
    safety of ribociclib and belinostat combination

  2. Progression Free Survival (PFS) [ Time Frame: 36 months ]
    assess efficacy

  3. Objective Response Rate (ORR) [ Time Frame: 36 months ]
    assess efficacy



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

For dose escalation cohorts only:

- Pathologically confirmed breast cancer with the following features:

  • Measurable disease by RECIST 1.1;
  • ER and PR ≤ 1% by immunohistochemistry;
  • Her-2/neu negative (0 or 1+ by immunohistochemistry OR not-amplified by CAP/ASCO standards);
  • Metastatic or unresectable and locally advanced and not amenable to treatment with curative intent, in the opinion of the enrolling investigator.

OR --Pathologically confirmed serous ovarian cancer that is recurrent and is unresectable, in the opinion of the enrolling investigator.

For dose expansion cohort only:

- Pathologically confirmed breast cancer with the following features:

  • Measurable disease by RECIST 1.1;
  • ER and PR ≤ 1% by immunohistochemistry;
  • Her-2/neu negative (0 or 1+ by immunohistochemistry OR not-amplified by CAP/ASCO standards);
  • Metastatic or unresectable and locally advanced and not amenable to treatment with curative intent, in the opinion of the enrolling investigator.

For all patients:

  • Age ≥ 18.
  • ECOG performance Status ≤ 2.
  • Able to swallow pills.
  • Adequate organ function as defined as:

    • Hematologic:

      • ANC > 1,500/mm3
      • Platelets > 100,000/mm3
      • Hemoglobin > 9g/dL
    • Hepatic:

      • Serum bilirubin levels ≤1.5 mg/dL. Higher levels are acceptable if these can be attributed to active hemolysis or ineffective erythropoiesis. Bilirubin above 1.5mg/dL due to Gilbert's is still excluded.
      • Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 2.5 X upper limit of normal.
      • AST(SGOT)/ALT(SGPT) ≤ 5 × institutional ULN for patients with liver metastasis.
      • Alkaline phosphatase < 2.5 X upper limit of normal, unless bone metastasis is present in the absence of liver metastasis
    • Renal:

      • Serum creatinine levels ≤1.5 mg/dL
      • Patient must have the following laboratory values within normal limits or corrected to within normal limits with supplements before the first dose of study medication:

        • Potassium
        • Magnesium
        • Total Calcium (corrected for serum albumin)
    • Coagulation ---INR ≤1.5 (unless the patient is receiving anticoagulants and the INR is within the therapeutic range of intended use for that anticoagulant within 7 days prior to the first dose of study drug)
  • Presence of ≥ 1 metastatic sites of disease that can be safely accessed for biopsy and patient willingness to undergo fresh tissue biopsies of up to 3 lesions.
  • Negative serum or urine pregnancy test at screening for women of childbearing potential.
  • Agrees to continue use of approved birth control for at least 6 months after receiving the last dose of study drugs. See section 7.3 for list of approved birth control methods.
  • Able to provide informed consent and have signed an approved consent form that conforms to federal and institutional guidelines.

Exclusion Criteria:

  • Previous use of CDK 4/6 or HDAC inhibitors for cancer treatment
  • Major surgery, radiotherapy, anticancer therapy, or investigational agents ≤ 4 weeks of treatment day 1 or ≤5 half-lives, whichever is shorter.
  • Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease unless determined by the treating physician that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy.
  • Medical condition that in the opinion of the enrolling investigator would require the use of valproic acid within ≤ 5 days of the first dose of belinostat or while on study.
  • Active infection requiring systemic therapy.
  • History of allergy or hypersensitivity to belinostat, ribociclib, or their binders.
  • Uncontrolled arrhythmia, congestive heart failure or angina. Patients who have had a myocardial infarction, symptomatic pericarditis, or cardiac surgery should be at least 6 months from the event and free of active symptoms
  • Known left ventricular ejection fraction < 50%. (Echocardiogram is not required for study entry)
  • Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block)
  • Congenital long QT syndrome.
  • Baseline QTcF>450 msec. The heart rate on the qualifying ECG must be between 50 and 90 BPM.
  • Concurrent use of medication known to inhibit UGT1A1. Patients currently taking these medications must have discontinued ≥7 days prior to treatment day 1.
  • Concurrent use of herbal supplements, unless approved by the prinicipal investigator. Patients currently taking herbal supplements must have discontinued ≥ 7 days prior to treatment day 1.
  • Concurrent use of medication with a known risk of inducing Torsades de Pointes (on the known risk list of crediblemeds.org) that cannot be discontinued or switched to a different medication ≥ 7 days prior to starting the study drug.
  • Unresolved diarrhea ≥ Grade 2, per CTCAE v5.0.
  • Use of any of the following substances ≤ 7 days prior to the start of the treatment:

    • Known strong and moderate inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pomelos, star-fruit, and Seville oranges.
    • Medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.
  • Patient is currently receiving warfarin or other coumarin derived anti-coagulant, for treatment, prophylaxis or otherwise.

    --Note: Therapy with heparin, low molecular weight heparin (LMWH), an oral factor Xa inhibitor, an oral direct thrombin inhibitor, or fondaparinux is allowed.

  • Impaired GI function that may alter absorption of medicines, such as uncontrolled inflammatory bowel disease, uncontrolled vomiting, or major stomach or small bowel resection.
  • Pregnant or breast feeding
  • Women of child-bearing potential defined as all women physiologically capable of becoming pregnant or men whose female partner is of child-bearing potential, unless they are using highly effective methods of contraception during the study treatment and for 6 months after stopping the treatment. Highly effective contraception methods include:

    • Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
    • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
    • Male partner sterilization (at least 6 months prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient and the success of the vasectomy must be medically confirmed as per local practice.
    • Placement of an intrauterine device (IUD).
    • Use of hormonal contraception plus a barrier contraceptive.
  • Known HIV infection with a detectable viral load within 6 months of the anticipated start of treatment.

Note: Patients on effective anti-retroviral therapy with an undetectable viral load within 6 months of the anticipated start of treatment are eligible for this trial.

  • Known chronic hepatitis B virus (HBV) or hepatitis C virus infection with a detectable viral load.

    --Note: Patients with an undetectable HBV viral load on appropriate suppressive therapy are eligible. Patients with an undetectable HCV viral load are eligible.

  • Malignancy other than breast carcinoma or ovarian cancer (dose escalation) anticipated to need systemic treatment within 1 year in the opinion of the enrolling investigator.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04315233


Contacts
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Contact: Janna Espinosa 801-585-0571 janna.espinosa@hci.utah.edu

Locations
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United States, Utah
Huntsman Cancer Institute Recruiting
Salt Lake City, Utah, United States, 84112
Contact: Janna Espinosa    801-585-0571    Janna.Espinosa@hci.utah.edu   
Sponsors and Collaborators
University of Utah
Novartis
Acrotech Biopharma
Investigators
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Principal Investigator: Theresa Werner, MD Huntsman Cancer Institute
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Responsible Party: University of Utah
ClinicalTrials.gov Identifier: NCT04315233    
Other Study ID Numbers: HCI130492
First Posted: March 19, 2020    Key Record Dates
Last Update Posted: November 10, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Belinostat
Antineoplastic Agents
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action