Clinical Trials /

Ribociclib + PDR001 in Breast Cancer and Ovarian Cancer

NCT03294694

Description:

This clinical trial is studying the drug Ribociclib (LEE011) in combination with an immunotherapy drug called PDR001 (a therapy that uses the body's own immune system to control cancer) as a possible treatment for metastatic hormone-receptor-positive (HR+), HER2-negative breast cancer (in combination with fulvestrant) or metastatic epithelial ovarian cancer. The names of the medications involved in this study are: - Ribociclib (LEE011) - PDR001 - Fulvestrant

Related Conditions:
  • Breast Carcinoma
  • Fallopian Tube Carcinoma
  • Ovarian Carcinoma
  • Peritoneal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Ribociclib + PDR001 in Breast Cancer and Ovarian Cancer
  • Official Title: A Phase 1 Study of the CDK4/6 Inhibitor Ribociclib (LEE011) in Combination With the PD-1 Inhibitor PDR001 in Patients With Metastatic Hormone Receptor-positive Breast Cancer and Metastatic Ovarian Cancer

Clinical Trial IDs

  • ORG STUDY ID: 17-285
  • NCT ID: NCT03294694

Conditions

  • Metastatic Hormone-Receptor-Positive (HR+) Breast Cancer
  • HER2-Negative Breast Cancer
  • Metastatic Epithelial Ovarian Cancer

Interventions

DrugSynonymsArms
RibociclibKisqali, LEE011, LEE-011Ribociclib and PDR001 (Cohort A)
PDR001Ribociclib and PDR001 (Cohort A)
FulvestrantFaslodex, ICI 182,780, ZD9238Ribociclib, PDR001 and Fulvestrant (Cohort B)

Purpose

This clinical trial is studying the drug Ribociclib (LEE011) in combination with an immunotherapy drug called PDR001 (a therapy that uses the body's own immune system to control cancer) as a possible treatment for metastatic hormone-receptor-positive (HR+), HER2-negative breast cancer (in combination with fulvestrant) or metastatic epithelial ovarian cancer. The names of the medications involved in this study are: - Ribociclib (LEE011) - PDR001 - Fulvestrant

Detailed Description

      -  This research study is a Phase I clinical trial, which tests the safety of an
           investigational combination of drugs (LEE011 with PDR001), and tries to define the
           appropriate dose of the above combination of investigational drugs to use for further
           studies. "Investigational" means that the intervention is being studied.

        -  The FDA (the U.S. Food and Drug Administration) has approved LEE011 as a treatment for
           hormone receptor positive metastatic breast cancer.

        -  The FDA has not approved PDR001 as treatment for any type of cancer.

        -  The FDA has approved fulvestrant as a treatment for hormone receptor positive metastatic
           breast cancer.

        -  When given separately these medications work in different ways to try and stop cancer
           cells from growing and spreading.

             -  LEE011 is a drug designed to block certain proteins called cyclin-dependent kinases
                (CDKs) that are required for cells to divide. These proteins may also control the
                ability of certain cancers to grow.

             -  PDR001 is an antibody. Antibodies are proteins usually produced by the body that
                help protect against foreign matter, such as bacteria and viruses. PDR001 blocks a
                protein called PD-1 which is present on cells called T-lymphocytes, which are
                involved in the immune response. PDR001 is being tested to see if it will allow the
                body's immune system to work against tumor cells. Other studies have shown that
                blocking PD-1 may result in reduced tumor cell growth in a variety of solid tumors.

             -  Fulvestrant is an estrogen receptor antagonist that is indicated for the treatment
                of postmenopausal women with HR+ MBC.

        -  In this research study, the investigators are looking for a safe and tolerable dose of
           LEE011 that can be given in combination with PDR001 for participants with metastatic
           hormone-receptor-positive (HR+), HER2-negative breast cancer (in combination with
           fulvestrant) or metastatic epithelial ovarian cancer.

      ELIGIBILITY FOR COHORT A DOSE ESCALATION (Ribociclib + PDR001):

        -  Hormone receptor (HR)-positive, HER2-negative metastatic breast cancer according to ASCO
           CAP Guidelines.

             -  Participants may have received any number of previous endocrine/hormonal lines of
                therapy in the metastatic setting, as long as the last dose is ≥ 14 days prior to
                registration.

             -  Participants may have received any number of prior lines of chemotherapy for
                advanced breast cancer as long as the last dose is ≥ 21 days prior to registration.

             -  Prior therapy with biologics and investigational drugs is allowed as long as the
                last dose is ≥ 21 days prior to registration.

             -  Prior CDK4/6 inhibition is allowed. Participants who have had prior ribociclib must
                have received treatment at full-dose without any dose-reductions. The last dose is
                required to be ≥ 21 days prior to registration

             -  No prior PD1/PDL1/CTLA4 inhibitors

             -  Participants may have received radiotherapy for palliative purposes but must have
                completed treatment ≥ 14 days prior to registration and not be experiencing > grade
                1 treatment related toxicities.

             -  Men are eligible, as long as on a GnRH agonist for at least 6 weeks prior to study
                entry. Men MUST remain on the GnRH agonist for the duration of protocol treatment.

             -  Evaluable or measurable disease by RECIST 1.1.

        -  Metastatic epithelial ovarian cancer, fallopian tube or peritoneal cancer. All
           histologies (including serous, mucinous, endometrioid, clear cell, MMMTs and mix
           histologies) and tumor grades are eligible

             -  Must have received a first-line platinum-based therapy and have disease that is
                platinum-resistant.

                --- Platinum-resistant disease is defined as disease relapse within 2 to 6 months
                of prior platinum-based chemotherapy.

             -  There is no limit to the number of lines of prior chemotherapy, biology or hormonal
                therapy regimens.

             -  No prior PD1/PDL1/CTLA4 inhibitors

             -  Evaluable or measurable disease by RECIST 1.1.

      ELIGIBILITY FOR COHORT A DOSE EXPANSION (Ribociclib + PDR001):

      - Metastatic epithelial ovarian cancer, fallopian tube or peritoneal cancer. All histologies
      (including serous, mucinous, endometrioid, clear cell, MMMTs and mixed histologies) and tumor
      grades are eligible.

        -  Must have received a first-line platinum-based chemotherapy regimen and have relapsed
           despite standard therapy.

        -  Must have received a first-line platinum-based therapy and have disease that is
           platinum-resistant.

           --- Platinum-resistant disease is defined as disease relapse within 2 to 6 months of
           prior platinum-based chemotherapy.

        -  There is no limit to the number of lines of prior chemotherapy, biology or hormonal
           therapy regimens.

        -  No prior CDK4/6 inhibitors.

        -  No prior PD1/PDL1/CTLA4 inhibitors.

        -  Measurable disease by RECIST 1.1.

        -  Participants with accessible tumor lesion(s) must be willing to undergo two research
           biopsies: one prior to treatment initiation and one after 7 weeks of protocol therapy.
           Participants who undergo an attempted on-treatment research biopsy and in whom
           inadequate tissue is obtained are still eligible to receive protocol therapy. They will
           not be required to undergo a repeat research biopsy attempt.

      ELIGIBILITY FOR COHORT B SAFETY RUN-IN (Ribociclib + PDR001 + Fulvestrant):

        -  Hormone receptor (HR)-positive, HER2-negative metastatic breast cancer according to ASCO
           CAP Guidelines.

        -  Men are eligible, as long as on a GnRH agonist for at least 6 weeks prior to study
           entry. Men MUST remain on the GnRH agonist for the duration of protocol treatment.

        -  Women must be postmenopausal as defined as:

           -- Age >60 years or Age >45 with intact uterus and amenorrhea for >12 consecutive months
           or Follicle stimulating hormone (FSH) levels within postmenopausal range according to
           the ranges established by the testing facility or Premenopausal women who have been on a
           GnRH agonist for at least 6 weeks prior to study entry. Women in this group MUST remain
           on the GnRH agonist for the duration of protocol treatment or Status post bilateral
           oophorectomy, after adequate healing post-surgery

        -  Evaluable or measurable disease by RECIST 1.1.

        -  Prior CDK4/6 inhibition is allowed. Participants who have had prior ribociclib must have
           received treatment at full-dose without any dose-reductions. The last dose is required
           to be ≥ 21 days prior to registration

        -  Prior hormonal therapy:

             -  Prior therapy with Fulvestrant is allowed

             -  Participants may have received any number of previous endocrine/hormonal lines of
                therapy in the metastatic setting, as long as the last dose is ≥ 14 days prior to
                registration.

        -  Participants may have received chemotherapy for advanced breast cancer as long as the
           last dose is ≥ 21 days prior to registration.

        -  Prior therapy with biologics and investigational drugs is allowed as long as the last
           dose is ≥ 21 days prior to registration.

        -  Participants may have received radiotherapy for palliative purposes but must have
           completed treatment ≥ 14 days prior to registration and not be experiencing > grade 1
           treatment related toxicities.

      ELIGIBILITY FOR COHORT B DOSE EXPANSION (Ribociclib + PDR001 + Fulvestrant):

        -  Hormone receptor (HR)-positive, HER2-negative metastatic breast cancer according to ASCO
           CAP Guidelines.

        -  Men are eligible, as long as on a GnRH agonist for at least 6 weeks prior to study
           entry. Men MUST remain on the GnRH agonist for the duration of protocol treatment.

        -  Women must be postmenopausal as defined as:

           -- Age >60 years or Age >45 with intact uterus and amenorrhea for >12 consecutive months
           or Follicle stimulating hormone (FSH) levels within postmenopausal range according to
           the ranges established by the testing facility or Premenopausal women who have been on a
           GnRH agonist for at least 6 weeks prior to study entry. Women in this group MUST remain
           on the GnRH agonist for the duration of protocol treatment or Status post bilateral
           oophorectomy, after adequate healing post-surgery

        -  Prior hormonal therapy:

             -  Must have progressed on an aromatase inhibitor in the metastatic setting or
                experienced disease recurrence within 6 months of completing adjuvant therapy with
                an aromatase inhibitor.

             -  Participants may have received any number of previous endocrine/hormonal lines of
                therapy in the metastatic setting, as long as the last dose is ≥ 14 days prior to
                registration.

             -  No prior fulvestrant

        -  Participants may have received up to one prior line of chemotherapy for advanced breast
           cancer as long as the last dose is ≥ 21 days prior to registration.

        -  Prior therapy with biologics and investigational drugs is allowed as long as the last
           dose is ≥ 21 days prior to registration.

        -  No prior CDK4/6 inhibitors

        -  No prior PD1/PDL1/CTLA4 inhibitors

        -  Participants may have received radiotherapy for palliative purposes but must have
           completed treatment ≥ 14 days prior to registration and not be experiencing > grade 1
           treatment related toxicities.

        -  Measurable disease by RECIST 1.1.

        -  Participants with accessible tumor lesion(s) must be willing to undergo two research
           biopsies: one prior to treatment initiation and one after 7 weeks of protocol therapy.
           Participants who undergo an attempted on-treatment research biopsy and in whom
           inadequate tissue is obtained are still eligible to receive protocol therapy. They will
           not be required to undergo a repeat research biopsy attempt.
    

Trial Arms

NameTypeDescriptionInterventions
Ribociclib and PDR001 (Cohort A)ExperimentalThe treatment regimen is defined as ribociclib + PDR001. Treatment will be administered on an outpatient basis. The study will use a 3 + 3 dose escalation design to determine the MTD/RP2D. Three to six evaluable patients will be enrolled in each cohort in the dose escalation phase. Once the RP2D of the combination of ribociclib + PDR001 is determined, there will be an expansion cohort. Cohort A expansion will assess the combination of ribociclib + PDR001 in 12 patients with metastatic ovarian cancer.
  • Ribociclib
  • PDR001
Ribociclib, PDR001 and Fulvestrant (Cohort B)ExperimentalThe treatment regimen is defined as ribociclib + PDR001 + fulvestrant . Treatment will be administered on an outpatient basis. There will be a safety run-in using the MTD/RP2D of ribociclib + PDR001 from Cohort A with the addition of fulvestrant in an initial 6-12 patients. Once the safety of the combination of ribociclib + PDR001 + fulvestrant is established, there will be an expansion cohort. Cohort B expansion will assess the combination of ribociclib + PDR001 + fulvestrant in 24 patients with hormone receptor-positive metastatic breast cancer (HR+ MBC).
  • Ribociclib
  • PDR001
  • Fulvestrant

Eligibility Criteria

        Inclusion Criteria

          -  Cohort A Dose Escalation (Ribociclib + PDR001) Eligibility can be found in Detailed
             Description Section

          -  Cohort B Safety Run-In (Ribociclib + PDR001 + Fulvestrant) Eligibility can be found in
             Detailed Description Section

          -  Cohort A Dose Expansion (Ribociclib + PDR001) Eligibility can be found in the Detailed
             Description Section

          -  Expansion Cohort B (Ribociclib + PDR001 + Fulvestrant Eligibility can be found in the
             Detailed Description Section

          -  ECOG Performance Status 0-1

          -  Participants must have normal organ and marrow function, as defined below:

               -  absolute neutrophil count ≥1,500/mcL

               -  platelets ≥100,000/mcL

               -  total hemoglobin ≥ 9 g/dL (may be post-transfusion)

               -  total bilirubin ≤1.5 x institutional ULN (IULN)

               -  AST(SGOT)/ALT(SGPT) ≤2.5 × IULN or ≤5 × IULN for participants with liver
                  metastases

               -  creatinine ≤1.5 x IULN or ≥ 60 ml/min/1.73m2 for subjects with creatinine levels
                  above institutional normal

               -  INR ≤ 1.5

               -  baseline QTc ≤ 450 msec

          -  Age > 18 years

          -  Women of child-bearing potential, defined as all women physiologically capable of
             becoming pregnant, must be willing to use a highly effective method of contraception
             during dosing and for 150 days after the last dose of PDR001.

        Note: 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 six 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

          -  For female participants, male sterilization (at least 6 months prior to screening).

          -  Placement of an intrauterine device (IUD) or intrauterine system (IUS).

               -  Sexually active males must be willing to use a condom during intercourse while
                  taking the study drug and for 21 days after stopping the study drug and should
                  not father a child in this period. A condom is required to be used also by
                  vasectomized men in order to prevent delivery of the drug via seminal fluid.

               -  Willingness to provide archival tumor samples. If sample is not available, a
                  biopsy should be considered in patients with safely accessible disease.
                  Participants who undergo an attempted research biopsy procedure for the purpose
                  of this protocol, and in whom inadequate tissue is obtained, are not required to
                  undergo repeat biopsy in order to continue on protocol.

               -  Ability to understand and the willingness to sign a written informed consent
                  document.

        Exclusion Criteria:

          -  Participants cannot have been treated on a prior interventional, investigational study
             within 2 weeks of the first dose of study treatment.

          -  Participants cannot receive treatment with any other investigational agents during
             protocol therapy.

          -  Use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GMCSF, M-CSF) ≤2
             weeks prior start of study drug. An erythroid stimulating agent is allowed as long as
             it was initiated at least 2 weeks prior to the first dose of study treatment.

          -  History of severe hypersensitivity reactions to other mAbs

          -  Participants requiring chronic treatment with systemic steroid therapy, other than
             replacement-dose steroids in the setting of adrenal insufficiency. Topical, inhaled,
             nasal and ophthalmic steroids are allowed.

          -  Participants receiving systemic treatment with any immunosuppressive medication (other
             than steroids as described above).

          -  Patient is currently receiving warfarin or other coumadin-derived anticoagulant for
             treatment, prophylaxis, or otherwise. Therapy with heparin, low molecular weight
             heparin (LMWH), coumadin or fondaparinux is allowed.

          -  Use of any live vaccines within 4 weeks of initiation of study treatment.

          -  Major surgery within 2 weeks of the first dose of study treatment (mediastinoscopy,
             insertion of a central venous access device, and insertion of a feeding tube are not
             considered major surgery).

          -  Participants with active autoimmune disease. Participants with vitiligo, type I
             diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring
             hormone replacement, psoriasis not requiring systemic treatment, or conditions not
             expected to recur in the absence of an external trigger are permitted to enroll.

          -  Presence of ≥ CTCAE grade 2 toxicity (CTCAE Grade 2 peripheral neuropathy and
             ototoxicity and any grade alopecia are allowed).

          -  Participants with uncontrolled intercurrent illness including, but not limited to:

               -  Clinically significant, uncontrolled heart disease and/or cardiac repolarization
                  abnormalities, including any of the following:

                    -  History of acute coronary syndromes (including myocardial infarction,
                       unstable angina, coronary artery bypass grafting, coronary angioplasty, or
                       stenting) or symptomatic pericarditis within 6 months prior to screening

                    -  History of documented congestive heart failure (New York Heart Association
                       functional classification III-IV)

                    -  Documented cardiomyopathy

                    -  Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple
                       Gated acquisition (MUGA) scan or echocardiogram (ECHO) within six months
                       prior to beginning protocol therapy.

                    -  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)

                    -  Long QT syndrome or family history of idiopathic sudden death or congenital
                       long QT syndrome, or any of the following:

                    -  Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia
                       or hypomagnesemia, history of cardiac failure, or history of clinically
                       significant/symptomatic bradycardia.

                    -  Concomitant use of medication(s) with a known risk to prolong the QT
                       interval and/or known to cause Torsades de Pointe that cannot be
                       discontinued (within 5 half-lives or 7 days prior to starting study drug) or
                       replaced by safe alternative medication

                    -  Systolic blood pressure (SBP) >160 mmHg or <90 mmHg at screening

                    -  Impairment of gastrointestinal function or who have gastrointestinal disease
                       that may significantly alter the absorption of study drugs (e.g., ulcerative
                       disease, uncontrolled nausea, vomiting, diarrhea or malabsorption syndrome).

                    -  Patient with liver disease and Child-Pugh score B or C.

               -  Individuals with a history of a second malignancy are ineligible except for the
                  following circumstances. Individuals with a history of other malignancies are
                  eligible if they have been disease-free for at least 5 years and are deemed by
                  the investigator to be at low risk for recurrence of that malignancy. Individuals
                  with the following cancers are eligible if diagnosed and treated within the past
                  5 years: cervical cancer in situ, and non-melanoma cancer of the skin. Patients
                  with other cancers diagnosed within the past 5 years and felt to be at low risk
                  of recurrence should be discussed with the study sponsor to determine
                  eligibility.

               -  Participants with known brain metastases may be enrolled in this study if
                  radiation therapy and/or surgery have been completed with a minimum of 4 weeks of
                  stable disease demonstrated on evaluation by MRI. Such participants must no
                  longer require treatment with corticosteroids or enzyme inducing anti-epileptic
                  medications for their CNS disease.

               -  Participants with current pneumonitis.

               -  Participants known to be HIV-positive or known to have active Hepatitis B or C.

               -  Pregnant or lactating women. A negative pregnancy test in women of child-bearing
                  potential must be documented within 7 days before the first dose of study
                  medication.

               -  Any condition that would prevent the patient's participation in the clinical
                  study due to safety concerns, compliance with clinical study procedures or
                  interpretation of study results.

               -  Active infection requiring systemic antibiotic therapy.

               -  Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment.
                  For cytotoxic agents that have major delayed toxicity, e.g. mitomycin C and
                  nitrosoureas, 4 weeks is indicated as washout period. For patients receiving
                  anticancer immunotherapies such as CTLA-4 antagonists, 3 weeks is indicated as
                  the washout period

               -  Participants who have received thoracic radiotherapy to lung fields ≤ 4 weeks
                  prior to starting the study treatment or patients who have not recovered from
                  radiotherapy-related toxicities. For all other anatomic sites (including
                  radiotherapy to thoracic vertebrae and ribs) radiotherapy ≤ 2 weeks prior to
                  starting the study treatment or has not recovered from radiotherapy-related
                  toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting
                  study treatment is allowed.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Cohort A: MTD/RP2D of the Combination of Ribociclib + PDR001
Time Frame:4 weeks
Safety Issue:
Description:Toxicity will be graded according to NCI CTCAE, Version 4.0.

Secondary Outcome Measures

Measure:Number of Participants with Adverse Events
Time Frame:All participants will be evaluable for toxicity from the time of their first treatment with any study agent until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
Safety Issue:
Description:Toxicity will be graded according to NCI CTCAE, Version 4.0.
Measure:Objective Response Rate
Time Frame:2 Years
Safety Issue:
Description:ORR is defined as the proportion of patients with complete response or partial response by RECIST 1.1 and immune-related RECIST (irRECIST)

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Metastatic Hormone-Receptor-Positive (HR+) Breast Cancer
  • HER2-Negative Breast Cancer
  • Metastatic Epithelial Ovarian Cancer

Last Updated

October 18, 2017