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* The 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.

* The 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).

Each treatment cycle lasts 28 days. Ribociclib, 1 time per day by mouth for 21 days, followed by 1-week of rest (28-day cycle)

Ribociclib

Each treatment cycle lasts 28 days. (PDR001) will be administered once every 28 days (by intravenous infusion) over about 30 minutes (or up to 2 hours, if necessary) for the first infusion and over about 30 minutes for all following infusions.

PDR001

Each treatment cycle lasts 28 days. Fulvestrant will be administered during Cycle 1 on days 1 and 15, and then on day 1 of each 28-day cycle thereafter.

Sara Tolaney, MD

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

* 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.
  * Patients 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.
* 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.

  * 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. 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.

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:

  * 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. 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.

Ribociclib + PDR001 in Breast Cancer and Ovarian Cancer

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

Toxicity will be graded according to NCI CTCAE, Version 4.0.

ORR is defined as the proportion of patients with complete response or partial response by RECIST 1.1 and immune-related RECIST (irRECIST)

Novartis

Dana-Farber Cancer Institute

Principal Investigator

Spots Global Cancer Trial Database for metastatic epithelial ovarian cancer