Ribociclib and Spartalizumab with or without Fulvestrant in Treating Patients with Hormone Receptor Positive and HER2 Negative Metastatic Breast Cancer or Metastatic Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Status: Active

Description

This phase I trial studies the side effects and best dose of ribociclib when given together with spartalizumab with or without fulvestrant in treating patients with hormone receptor positive and HER2 negative breast cancer that has spread to other places in the body (metastatic), or ovarian, fallopian tube, or primary peritoneal cancer that has spread to other places in the body (metastatic). Ribociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as spartalizumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs, such as fulvestrant, may lessen the amount of estrogen made by the body. Giving ribociclib and spartalizumab with or without fulvestrant may work better in treating patients with breast, ovarian, fallopian tube, or primary peritoneal cancer.

Eligibility Criteria

Inclusion Criteria

  • Cohort A Dose Escalation (Ribociclib + PDR001): Breast participants: * Hormone receptor (HR)-positive, HER2-negative metastatic breast cancer according to American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) guidelines * Men are eligible, as long as on a gonadotropin releasing hormone (GNRH) agonist for at least 4 weeks prior to study entry; men MUST remain on the GnRH agonist for the duration of protocol * Prior Chemotherapy: 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 first dose of study treatment.
  • Cohort A Dose Escalation (Ribociclib + PDR001): Ovarian participants: * Metastatic epithelial ovarian cancer, fallopian tube or peritoneal cancer; all histologies (including serous, mucinous, endometrioid, clear cell, malignant mixed Mullerian tumor [MMMT]s and mixed histologies) and tumor grades are eligible * Prior Chemotherapy: Participants may have received any number of prior lines of chemotherapy for metastatic disease, as long as the last dose is >= 21 days prior to first dose of study treatment ** 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
  • All Cohort A Dose Escalation Participants: * Prior hormonal therapy: Participants may have received any number of previous endocrine / hormonal lines of therapy in the metastatic setting (including prior fulvestrant), as long as the last dose is >= 14 days prior to first dose of study treatment * Prior biologics / investigational therapy: Prior therapy with biologics and investigational drugs is allowed, as long as the last dose is >= 21 days prior to first dose of study treatment * 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 first dose of study treatment * Treatment with prior PD1/PDL1/CTLA4 inhibitors is prohibited * Prior radiotherapy: Participants may have received radiotherapy for palliative purposes but must have completed treatment >= 14 days prior to first dose of study treatment and not be experiencing grade > 1 treatment-related toxicities * Evaluable or measurable disease by RECIST 1.1
  • Cohort B Safety Run-In (Ribociclib + PDR001 + Fulvestrant): Hormone receptor (HR)-positive, HER2-negative metastatic breast cancer according to ASCO CAP guidelines
  • Cohort B Safety Run-In (Ribociclib + PDR001 + Fulvestrant): Men are eligible, as long as on a GnRH agonist for at least 4 weeks prior to study entry; men MUST remain on the GnRH agonist for the duration of protocol treatment
  • Cohort B Safety Run-In (Ribociclib + PDR001 + Fulvestrant): 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 4 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
  • Cohort B Safety Run-In (Ribociclib + PDR001 + Fulvestrant): Evaluable or measurable disease by RECIST 1.1
  • Cohort B Safety Run-In (Ribociclib + PDR001 + Fulvestrant): 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 first study treatment
  • Cohort B Safety Run-In (Ribociclib + PDR001 + Fulvestrant): Treatment with prior PD1/PDL1/CTLA4 inhibitors is prohibited
  • Cohort B Safety Run-In (Ribociclib + PDR001 + Fulvestrant): Prior hormonal therapy: * Participants may have received any number of previous endocrine / hormonal lines of therapy (including prior fulvestrant) in the metastatic setting, as long as the last dose is >= 14 days prior to first dose of study treatment
  • Cohort B Safety Run-In (Ribociclib + PDR001 + Fulvestrant): Prior chemotherapy: * Participants may have received chemotherapy for advanced breast cancer as long as the last dose is >= 21 days prior to registration
  • Cohort B Safety Run-In (Ribociclib + PDR001 + Fulvestrant): Prior biologics / investigational therapy: * Prior therapy with biologics and investigational drugs is allowed, as long as the last dose is >= 21 days prior to first dose of study treatment
  • Cohort B Safety Run-In (Ribociclib + PDR001 + Fulvestrant): Prior radiotherapy; * Participants may have received radiotherapy for palliative purposes but must have completed treatment >= 14 days prior to first dose of study treatment and not be experiencing > grade 1 treatment related toxicities
  • 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
  • Cohort A Dose Expansion (Ribociclib + PDR001): Prior chemotherapy: * Participants may have received any number of prior lines of chemotherapy for metastatic disease, as long as the last dose is >= 21 days prior to first dose of study treatment ** 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 ** Must have received a first-line platinum-based chemotherapy regimen and have relapsed despite standard therapy
  • Cohort A Dose Expansion (Ribociclib + PDR001): Prior hormonal therapy: * 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 first dose of study treatment
  • Cohort A Dose Expansion (Ribociclib + PDR001): Prior biologics / investigational therapy: * Prior therapy with biologics and investigational drugs is allowed, as long as the last dose is >= 21 days prior to first dose of study treatment
  • Cohort A Dose Expansion (Ribociclib + PDR001): Prior radiotherapy: * Participants may have received radiotherapy for palliative purposes but must have completed treatment >= 14 days prior to first dose of study treatment and not be experiencing grade > 1 treatment-related toxicities
  • Cohort A Dose Expansion (Ribociclib + PDR001): Treatment with prior CDK4/6 inhibitors is prohibited
  • Cohort A Dose Expansion (Ribociclib + PDR001): Treatment with prior PD1/PDL1/CTLA4 is prohibited
  • Cohort A Dose Expansion (Ribociclib + PDR001): Measurable disease by RECIST 1.1 is required
  • Cohort A Dose Expansion (Ribociclib + PDR001): 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; if a biopsy-accessible participant has had a biopsy within 30 days of treatment initiation for clinical purposes, they may choose to submit an archived specimen from this procedure instead
  • Expansion Cohort B (Ribociclib + PDR001 + Fulvestrant): Hormone receptor (HR)-positive, HER2-negative metastatic breast cancer according to ASCO CAP guidelines
  • Expansion Cohort B (Ribociclib + PDR001 + Fulvestrant): Men are eligible, as long as on a GnRH agonist for at least 4 weeks prior to study entry; men MUST remain on the GnRH agonist for the duration of protocol treatment
  • Expansion Cohort B (Ribociclib + PDR001 + Fulvestrant): 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 4 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
  • Expansion Cohort B (Ribociclib + PDR001 + Fulvestrant): Prior hormonal therapy: * 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 first dose of study treatment * Treatment with prior fulvestrant is prohibited
  • Expansion Cohort B (Ribociclib + PDR001 + Fulvestrant): Prior chemotherapy: * 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 first dose of study treatment
  • Expansion Cohort B (Ribociclib + PDR001 + Fulvestrant): Prior biologics / investigational therapy: * Prior therapy with biologics and investigational drugs is allowed, as long as the last dose is >= 21 days prior to first dose of study treatment
  • Expansion Cohort B (Ribociclib + PDR001 + Fulvestrant): Prior radiotherapy: * Participants may have received radiotherapy for palliative purposes but must have completed treatment >= 14 days prior to first dose of study treatment and not be experiencing grade > 1 treatment-related toxicities
  • Expansion Cohort B (Ribociclib + PDR001 + Fulvestrant): Treatment with prior CDK4/6 inhibitors are prohibited
  • Expansion Cohort B (Ribociclib + PDR001 + Fulvestrant): Treatment with prior PD1/PDL1/CTLA4 inhibitors are prohibited
  • Expansion Cohort B (Ribociclib + PDR001 + Fulvestrant): Measurable disease by RECIST 1.1 is required
  • Expansion Cohort B (Ribociclib + PDR001 + Fulvestrant): 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; If a biopsy-accessible participant has had a biopsy within 30 days of treatment initiation for clinical purposes, they may choose to submit an archived specimen from this procedure instead
  • All Cohorts
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Hemoglobin >= 9 g/dL (may be post-transfusion)
  • International normalized ratio (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)
  • Estimated glomerular filtration rate (eGFR) >= 30 mL/min/1.73 by either Cockcroft-Gault or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
  • Total bilirubin =< upper limit of normal (ULN) except for patients with Gilbert’s syndrome who may only be included if the total bilirubin is =< 3.0 x ULN
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 2.5 x ULN, except for patients with liver metastasis, who are only included if the AST is =< 5 x ULN
  • Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN, except for patients with liver metastasis, who are only included if the ALT is =< 5 x ULN
  • Corrected QT using Fridericia's formula (QTcF) interval at screening =< 450 msec (using Fridericia’s correction)
  • Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective methods 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); the vasectomized male partner should be the sole partner for that patient ** Use of oral, injected, or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception
  • Sexually active males must be willing to use a condom during intercourse while taking the study drug and for 150 days after stopping the study drug and should not father a child in this period; a condom is required to be used 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

  • History of allogenic bone marrow or solid organ transplant
  • 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. granulocyte colony-stimulating factor [G-CSF], granulocyte macrophage colony stimulating factor [GMCSF], macrophage colony-stimulating factor [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 monoclonal antibodies (mAbs) or a known hypersensitivity to any of the excipients of ribociclib
  • Participants requiring chronic treatment with systemic steroid therapy, other than replacement-dose steroids in the setting of adrenal insufficiency within 7 days of treatment initiation; topical, inhaled, nasal and ophthalmic steroids are allowed; physiologic doses of steroids are acceptable
  • Participants receiving systemic treatment with any immunosuppressive medication (other than steroids as described above)
  • Participants may not be currently receiving anticoagulation with coumadin for treatment or prophylaxis; therapy with heparin, low molecular weight heparin (LMWH), 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 grade >= 2 Common Terminology Criteria for Adverse Events (CTCAE) 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 documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry ** Documented cardiomyopathy ** Left ventricular ejection fraction (LVEF) < 50% as determined by multiple-gated acquisition (MUGA) scan or echocardiogram (ECHO) ** 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) *** Inability to determine the QTcF interval ** Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II and third degree AV block) ** Systolic blood pressure (SBP) > 160 or < 90 mmHg ** Patients that have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g. uncontrolled ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection with known malabsorption) ** Patient with liver disease and Child-Pugh score B or C
  • Patients currently receiving a prohibited concomitant therapy that cannot be discontinued 7 days prior to the initiation of study treatment
  • 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 a 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 * Individuals with other cancers diagnosed within the past 5 years and felt to be at a 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 magnetic resonance imaging (MRI); such participants must no longer require treatment with corticosteroids or enzyme inducing anti-epileptic medications for their central nervous system (CNS) disease
  • Participants with current pneumonitis or interstitial lung disease
  • Participants known to be human immunodeficiency virus (HIV)-positive or known to have active hepatitis B or C; Note: Participants in whom hepatitis C virus (HCV) infection resolved spontaneously (positive HCV antibodies without detectable HCV-ribonucleic acid [RNA]) or those that achieved a sustained virological response after antiviral treatment and show absence of detectable HCV RNA >= 6 months (with the use of IFN-based regimens) after cessation of antiviral treatment are eligible
  • Pregnant or lactating women; a negative pregnancy test in women of childbearing 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
  • 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

Locations & Contacts

Massachusetts

Boston
Brigham and Women's Hospital
Status: Active
Contact: Christina Isabella Herold
Phone: 617-632-3800
Email: cherold@partners.org
Dana-Farber Cancer Institute
Status: Active
Contact: Christina Isabella Herold
Phone: 617-632-3800
Email: cherold@partners.org
Massachusetts General Hospital Cancer Center
Status: Active
Contact: Aditya Bardia
Phone: 617-643-2208

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. Determine the safety, tolerability, maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of ribociclib and spartalizumab (PDR001) in patients with metastatic ovarian cancer. (Cohort A)

II. Determine the safety, tolerability, maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of ribociclib and PDR001 and fulvestrant in patients with hormone receptor positive (HR+) metastatic breast cancer (MBC). (Cohort B)

SECONDARY OBJECTIVES:

I. Preliminary assessment of anti-tumor activity of the combination of ribociclib and PDR001 (overall response rate [ORR] by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 and immune-related RECIST [irRECIST]) in patients with metastatic ovarian cancer. (Cohort A)

II. Preliminary assessment of anti-tumor activity of the combination of ribociclib and PDR001 and fulvestrant (ORR by RECIST 1.1 and irRECIST) in patients with HR+ MBC. (Cohort B)

CORRELATIVE SCIENCE OBJECTIVES:

I. Characterize a broad array of immune markers in HR+ MBC (based on histology, protein expression, messenger ribonucleic acid [mRNA] expression, and genomic analysis).

II. Explore how different immunosuppressive and/or immune-stimulating immune marker profiles at baseline correlate with disease response to therapy, as assessed by objective response rate via RECIST 1.1 and irRECIST (ORR).

III. Characterize changes in immune marker profile in peripheral blood mononuclear cells (PBMCs) from baseline to over the course of trial therapy.

IV. Explore whether induction of changes in the immunosuppressive and/or immune-stimulating immune marker profile in PBMCs at baseline compared to on-therapy correlates with disease response to therapy (ORR).

V. Investigate whether there is an immune marker in circulating PBMCs that corresponds to tumor infiltrating lymphocyte (TIL) percentage in baseline tumor.

VI. In the cohort of patient who undergo metastatic site biopsy: to explore whether the number and/or type of mutations identified using Nanostring, a next generation sequencing (NGS) panel, is correlated with patient outcomes (ORR).

VII. In the cohort of patients who undergo re-biopsy at approximately week 7 of treatment: To characterize changes in a broad array of immune markers from baseline to 7 weeks on trial therapy, and explore changes in the tumor microenvironment that correlate with disease response to therapy (ORR).

VIII. In the cohort of patients who undergo optional re-biopsy at time of disease progression: Characterize further changes in immune markers and the tumor microenvironment in order to explore mechanisms of resistance to both CDK4/6 inhibition and immunotherapy.

IX. To explore whether the number and/or type of mutations identified using a next generation sequencing (NGS) panel (Oncopanel) is correlated with patient outcomes (ORR).

X. To characterize the structure and function of the gut microbiome in patients with breast cancer prior to starting this clinical trial.

XI. To determine whether pre-treatment characteristics of the structure and function of the gut microbiome in patients with breast cancer is associated with disease response to therapy (ORR).

XII. To characterize changes in the structure and function of the gut microbiome of patients with breast cancer after two cycles of study therapy compared to baseline.

XIII. To determine whether changes in the overall diversity of the gut microbiome, estimated by the Shannon Index, of patients with breast cancer after two cycles of therapy is associated with ORR.

XIV. To determine if the abundance or functional profile of specific gut bacteria are associated with ORR.

OUTLINE: This is a dose-escalation study of ribociclib. Patients are assigned to 1 of 2 cohorts.

COHORT A: Patients receive ribociclib orally (PO) daily on days 1-21 and spartalizumab intravenously (IV) over 30 minutes (up to 2 hours) on day 1. Treatment repeat every 28 days in the absence of disease progression or unacceptable toxicity.

COHORT B: Patients receive ribociclib and spartalizumab as in Cohort A. Patients also receive fulvestrant intramuscularly (IM) on days 1 and 15 of cycle 1 and on day 1 of subsequent cycles. Treatment repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Christina Isabella Herold

Trial IDs

Primary ID 17-285
Secondary IDs NCI-2017-02349
Clinicaltrials.gov ID NCT03294694