Ribociclib and Everolimus in Treating Patients with Metastatic Pancreatic Cancer That is Refractory to Chemotherapy

Status: Active

Description

This phase I / II trial studies the side effects and best dose of ribociclib and to see how well it works when given together with everolimus in treating patients with pancreatic cancer that has spread to other places in the body (metastatic) and does not respond to chemotherapy treatment (refractory). Ribociclib and everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Eligibility Criteria

Inclusion Criteria

  • Histologically confirmed mPAC (mixed histology is acceptable as long as the predominant histology is pancreatic adenocarcinoma)
  • Patient must consent to two mandatory biopsies and have tumor amenable to biopsy * Tumor biopsies are mandatory UNLESS the patient has been evaluated for a biopsy in consultation with radiology in good faith, and there is a determination that an attempt at a biopsy would cause undue risk to the patient
  • Measurable disease by RECIST v1.1 criteria (tumor >= 1 cm in longest diameter on axial image on computed tomography [CT] or magnetic resonance imaging [MRI] and/or lymph node(s) >= 1.5 cm in short axis on CT or MRI) on baseline imaging
  • Documented progression of disease on at least one 5-FU-based regimen and at least one GEM-based regimen for metastatic disease (progression during or within 3 months of the completion of adjuvant therapy is acceptable)
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2
  • Subjects with no brain metastases or a history of previously treated brain metastases who have been treated by surgery or stereotactic radiosurgery (SRS) at least 4 weeks prior to enrollment and have a baseline MRI that shows no evidence of active intracranial disease
  • Patients with available standard 12-lead electrocardiography (ECG) with the following parameters at screening (defined as the mean of the triplicate ECGs): * Fridericia's correction formula (QTcF) interval at screening < 450 msec * Resting heart rate 50-90 beats per minute (bpm)
  • Absolute neutrophil count (ANC) >= 1,500/mm^3
  • Platelets >= 100 x 10^9/L
  • Hemoglobin >= 9.0 g/dL * Patients may have a transfusion of red blood cells to meet the hemoglobin requirement
  • Serum creatinine =< 1.5 x upper normal limit of institution's normal range or creatinine clearance >= 50 mL/min/1.73 m^2 for subjects with creatinine levels above institutional normal
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x the upper normal limit of institution's normal range; for subjects with liver metastases, AST and ALT < 5 x the upper normal limit of institution's normal range are acceptable as long as there is no persistent nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia
  • Total bilirubin =< 1.5 x the upper normal limit of institution's normal range; for subjects with liver metastases, total bilirubin > 1.5 - 3.0 x the upper normal limit of institution's normal range are acceptable as long as there is no persistent nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia
  • Partial thromboplastin time (PTT) must be =< 1.5 x upper normal limit of institution's normal range and INR (international normalized ratio) =< 1.5; subjects on anticoagulant (such as warfarin) will be permitted to enroll as long as the INR is in the acceptable therapeutic range as determined by the investigator
  • Potassium, total calcium (corrected for serum albumin), magnesium, sodium and phosphorus within normal limits for the institution or corrected to within normal limits with supplements before first dose of study medication
  • Patients must have fully recovered from all effects of surgery; patients must have had at least two weeks after minor surgery and four weeks after major surgery before starting therapy; minor procedures requiring “Twilight” sedation such as endoscopies or mediport placement may only require a 24-hour waiting period, but this must be discussed with an investigator
  • Patients and their partners must avoid pregnancy during the trial, and for 21 days after stopping the study medications * Avoidance of pregnancy may 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 * Eligible female patients may have undergone 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, patients are eligible only when the reproductive status of the woman has been confirmed by follow up hormone level assessment * Eligible male patients and male partners of patients must also agree to avoid pregnancy during the trial, and for 21 days after stopping the study medications * Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to initiation of treatment and/or postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential
  • Patient is capable of swallowing pills whole
  • Patient is capable of understanding and complying with parameters as outlined in the protocol and able to sign and date the informed consent, approved by the Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures

Exclusion Criteria

  • Patients previously exposed to, intolerant of, or ineligible for CDK inhibitors, mTOR inhibitors, and/or their combination
  • Prior anti-tumor therapy within 3 weeks of cycle 1 day 1 (anti-tumor therapy defined as, but is not limited to, anti-cancer agents (cytotoxic chemotherapy, immunotherapy, and biologic therapy), radiotherapy, and investigational agents), the “wash-out period”
  • Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, etc.)
  • Women who are pregnant or breastfeeding
  • Concurrent use of CYP3A4 inhibiting or activating medications
  • Concurrent use of an angiotensin-converting enzyme (ACE) inhibitor (increased risk of angioedema with ACE inhibitors administered in combination with everolimus, seen in approximately 6.8% of patients)
  • Psychiatric illness or social situation that would limit compliance with study requirements
  • Patient has a concurrent malignancy or malignancy within 3 years prior to starting study drug, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer
  • Patients with central nervous system (CNS) involvement unless they meet ALL of the following criteria: * At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment * Clinically stable CNS tumor at the time of screening and not receiving steroids and/or enzyme-inducing anti-epileptic medications for brain metastases
  • Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
  • Patient has a known history of human immunodeficiency virus (HIV) infection or chronic, active hepatitis B (testing not mandatory)
  • 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) at screening * 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 * Inability to determine the QT interval on screening (QTcF, using Fridericia’s correction) * Systolic blood pressure (SBP) > 160 mmHg or < 90 mmHg at screening
  • Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to starting study drug: * Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges * That have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5 * Herbal preparations/medications, dietary supplements
  • Patient is currently receiving or has received systemic corticosteroids =< 2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment * Note: The following uses of corticosteroids are permitted: single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular)

Locations & Contacts

District of Columbia

Washington
MedStar Georgetown University Hospital
Status: Active
Contact: Michael Jon Pishvaian
Phone: 202-444-2144
Email: pishvaim@georgetown.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose (RP2D) of ribociclib (LEE011) in the combination with everolimus in patients with metastatic pancreatic adenocarcinoma (mPAC) refractory to fluorouracil (5-FU)- and gemcitabine (GEM)-based chemotherapy. (Phase I)

II. To determine the progression-free survival (PFS) rate at 8 weeks (PFS8 weeks) to assess the clinical efficacy of the combination of LEE011 and everolimus in patients with mPAC refractory to 5-FU- and GEM-based chemotherapy. (Phase II)

SECONDARY OBJECTIVES:

I. To determine the median progression-free survival (mPFS) of patients treated with the combination of LEE011 and everolimus in patients with mPAC refractory to chemotherapy.

II. To determine the median overall survival (mOS) of patients treated with the combination of LEE011 and everolimus in patients with mPAC refractory to chemotherapy.

III. To determine the best overall response rate (ORR), the largest percent decrease in tumor size from baseline as measured by expert radiologists using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria, defined as the proportion of patients with a complete response (CR) or partial response (PR), of the combination of LEE011 and everolimus in patients with mPAC refractory to chemotherapy.

IV. To determine the safety and tolerability of the combination of LEE011 and everolimus in patients with mPAC refractory to chemotherapy.

EXPLORATORY OBJECTIVES:

I. To correlate the PFS8 weeks to correlative scientific markers, including the analysis of tumor biopsies and blood-based markers, including RB, phosphorylation (p)RB, p16, cyclin D1, Ki67, MCM7, and pS6 levels by immunohistochemistry.

II. To screen for use a targeted sequencing approach for genetic lesions observed in pancreatic cancer that includes KRAS, SMAD4, TP53, CDKN2A as well as other commonly mutated cancer genes.

III. To assess blood for the analysis of circulating tumor deoxyribonucleic acid (DNA) as a surrogate marker of disease burden.

OUTLINE: This is a phase I, dose-escalation study of ribociclib followed by a phase II study.

Patients receive ribociclib orally (PO) once daily (QD) on days 1-21 and everolimus PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for up to 24 months.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
MedStar Georgetown University Hospital

Principal Investigator
Benjamin Adam Weinberg

Trial IDs

Primary ID 2016-0232
Secondary IDs NCI-2017-02168
Clinicaltrials.gov ID NCT02985125