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

NOT ENROLLING
Protocol # :
17-285
Conditions
Metastatic Hormone-Receptor-Positive (HR+) Breast Cancer
HER2-negative Breast Cancer
Metastatic Epithelial Ovarian Cancer
Phase
I
Disease Sites
Breast
Ovary
Principal Investigator
Tolaney, Sara, M
Site Investigator
Bardia, Aditya
Site Research Nurses
Abraham, Elizabeth
Beardslee, Brian
Beeler, Maureen
Caradonna, Lisa
Caramella, Anne
Carrier, Amy
Carrier, Amy
DeGonge, Danielle
Germon, Victoria
Gormley, Jill, Kathleen
Habin, Karleen, R.
Hassinger, Faith
Hedglin, Jennifer
Hewes, Julia
Huff, Kimberly
Kasparian, Elizabeth
Lehnus, Jaclyn
Livengood, Amanda
Lundquist, Debra
Marchetti, Kelly
McCarthy, Elizabeth, Ann
Morse, Linda, K.
O'Neil, Kelly
Padden, Sarah
Patchel, Rachel, Alexandra
Powers, Allison
QUINN, NICHOLAS
Roche, Kathleen, A.
Rutter, Morgan
Shellock, Maria
Wong, Christine

Trial 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

Eligibility Requirements

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

- estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 by either
Cockcroft-Gaultor CKD-EPI

- 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 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).

- 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.

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