Clinical Trials /

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

NCT04315233

Description:

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.

Related Conditions:
  • Breast Carcinoma
  • Ovarian Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Ribociclib&Belinostat In Patients w Metastatic Triple Neg Breast Cancer & Recurrent Ovarian Cancer w Response Prediction By Genomics
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: HCI130492
  • NCT ID: NCT04315233

Conditions

  • Metastatic Breast Cancer
  • Recurrent Ovarian Carcinoma

Interventions

DrugSynonymsArms
RibociclibTreatment: all patients
BelinostatTreatment: all patients

Purpose

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.

Detailed Description

      We hypothesize that ribociclib plus belinostat will be a well-tolerated and demonstrate
      activity in women with metastatic triple-negative breast or recurrent ovarian cancers.

      This trial combines two targeted agents, a CDK inhibitor and a lysine deacetylase (DAC)
      inhibitor for use as the first targeted treatment for metastatic triple-negative breast
      cancer. This in itself would be a leap forward for women who currently endure sequential
      treatment with cytotoxic chemotherapies. However, we will also be using samples from this
      trial in NIH-funded research on clonal evolution and geographic heterogeneity in breast
      cancer. Blockade of CDK4/6 and of lysine deacetylases (DAC) are both promising treatments for
      breast cancer. DAC inhibitors have been shown to have single-agent activity against
      triple-negative breast cancer in vivo, possibly through decreasing EMT, decreasing migration,
      and decreasing metastasis [6, 7] CDK4/6 inhibitor monotherapy causes cell cycle arrest and
      tumor regression in triple-negative breast cancer models. [8, 9] However, neither approach
      has been successfully translated into clinical use as a monotherapy.

      There are several lines of evidence demonstrating that inhibiting DAC increases the
      sensitivity of breast cancer to CDK4/6 inhibition. Recently, we showed that inhibitors of
      cell cycle progression, including CDKN1A, CDKN1C, CDKN2B, and CDKN2D, are increased by DAC
      inhibition in breast cancer cell lines, including triple-negative cell lines. [10] Others
      have shown cell cycle arrest by DAC inhibitors due to increases in p21 or decreases in CDK2
      and cyclin A. [11-13] We also see an increase in RB1 expression in breast cancer cell lines.
      In the TCGA breast cancer analysis, RB1 was frequently down-regulated but not mutated or lost
      in triple-negative breast cancer. [14] Therefore, we hypothesized that DAC inhibition would
      increase the sensitivity of breast cancer to CDK4/6 inhibition. We first tested this
      hypothesis in a small panel of cell lines. We showed and published that all showed synergy
      between a CDK4/6 inhibitor (PD-0322991) and DAC inhibitors. [10] Since then, we have tested
      the combination of the DAC inhibitor vorinostat and the CDK4/6 inhibitor PD-322991 in a
      larger panel of cell lines and have shown at least additivity in most triple-negative cell
      lines. Indeed, it seems that those cancers least sensitive to CDK4/6 inhibition may benefit
      the most from co-treatment with a DAC inhibitor.

      Recently, we investigated ribociclib and belinostat in six triple-negative breast cancer cell
      lines. All 6 cell lines showed growth inhibition with belinostat and panobinostat. Synergy
      was seen in four of the six cell lines at multiple doses.

      We have also recently completed an analysis on a window of opportunity trial of the DAC
      inhibitor high-dose valproic acid, in breast cancer.[15] In that study, women were treated
      with valproic acid for one week before definitive therapy began. Fifty percent of women with
      triple-negative breast cancers had a significant decrease in Ki-67 with one week of valproic
      acid, providing proof of principle biologic activity of DAC inhibition in triple-negative
      breast cancer. (By contrast, no HER2 positive tumor had a decrease in Ki-67 with valproic
      acid treatment.) Given the genomic similarities between serous ovarian cancer and
      triple-negative breast cancer seen in the TCGA and pan-cancer analyses [16], we have chosen
      to include ovarian cancers in the dose-escalation component to increase accrual rate but not
      in the dose-expansion.

      Neither CDK4/6 inhibition nor DAC inhibition have a well-defined predictive biomarker to
      determine which cancers will respond and which will not. Because of the complex genomic
      effects of inhibition of the 11 DACs and the multiple targets of DACs, including histones,
      p53, etc, it is unlikely that a single gene or protein alteration will predict sensitivity.
      We have published a method for predicting sensitivity to targeted drugs using genome-wide
      gene expression analysis. [17] After demonstrating proof of principle by accurately
      predicting sensitivity to vemurafenib, we developed a genomic biomarker for the DAC inhibitor
      valproic acid. We then validated that this biomarker predicted sensitivity in vitro and in
      vivo. In the window of opportunity discussed above, our genomic signature had an AUC of 0.66
      for predicting decreased Ki-67 with one week of treatment with valproic acid. We will develop
      a similar multi-gene gene expression based biomarker for the combination of ribociclib and
      belinostat.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment: all patientsExperimentalRibociclib 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.
  • Ribociclib
  • Belinostat

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:MTD of ribociclib and belinostat combination
Time Frame:C1D1 to C2D1 (each cycle is 28 days)
Safety Issue:
Description:incidence of DLTs during the defined DLT period

Secondary Outcome Measures

Measure:frequency and characterization of AEs and SAEs
Time Frame:36 months
Safety Issue:
Description:safety of ribociclib and belinostat combination
Measure:Progression Free Survival (PFS)
Time Frame:36 months
Safety Issue:
Description:assess efficacy
Measure:Objective Response Rate (ORR)
Time Frame:36 months
Safety Issue:
Description:assess efficacy

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Utah

Last Updated

September 23, 2020