Cobimetinib or Olaparib in Treating Patients with Resectable Pancreatic Cancer

Status: Active

Description

This phase II trial feasibility study aims to determine how cobimetinib or olaparib works in patients with pancreatic cancer that can be removed by surgery. Validation of cobimetinib and olaparib molecular targets will be explored by comparing pre-treatment biopsies with post-treatment resection specimens. This knowledge will help design future biomarker driven trials to determine whether giving cobimetinib or olaparib will work better than standard treatments in patients with pancreatic cancer.

Eligibility Criteria

Inclusion Criteria

  • Ability to understand and the willingness to sign a written informed consent document
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
  • Clinically-confirmed diagnosis of non-metastatic, adenocarcinoma of the pancreas
  • At time of screening, must have resectable pancreatic adenocarcinoma (as defined by institutional guidelines)
  • Must be deemed fit to undergo planned curative resection as determined by institutional standards
  • No history of previous chemotherapy
  • Based on available imaging, participant must have at least one disease lesion that can be biopsied in accordance with institutional standards
  • Hemoglobin >= 10.0 g/dL with no blood transfusion within 28 days of starting treatment (at time of registration and within 4 weeks prior to initiating window treatment)
  • White blood cells (WBC) > 3 x 10^9/L (at time of registration and within 4 weeks prior to initiating window treatment)
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (> 1500 per mm^3) (at time of registration and within 4 weeks prior to initiating window treatment) * May be waived on a case-by-case basis for patient populations recognized to have normal baseline values below this level
  • Platelet count >= 100 x 10^9/L (> 100,000 per mm^3) (at time of registration and within 4 weeks prior to initiating window treatment)
  • Creatinine =< 1.5 x upper limit of normal (ULN), OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min/1.73m^2 for participants with creatinine levels > 1 x institutional ULN (at time of registration and within 4 weeks prior to initiating window treatment) * Creatinine clearance should be calculated per institutional standard. For participants with a baseline calculated creatinine clearance below normal institutional laboratory values, a measured baseline creatinine clearance should be determined. Individuals with higher values felt to be consistent with inborn errors of metabolism will be considered on a case-by-case basis
  • Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) (at time of registration and within 4 weeks prior to initiating window treatment)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (at time of registration and within 4 weeks prior to initiating window treatment)
  • Participants must be willing to undergo one mandatory on-study tumor biopsies prior to initiating window treatment (i.e., cobimetinib or olaparib)
  • Participant is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
  • Participant must be able to swallow tablets or capsules. A participant with any gastrointestinal disease that would impair ability to swallow, retain, or absorb drug is not eligible
  • Female participants of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  • Female participants of childbearing potential agree to use adequate methods of contraception starting with the first dose of study therapy through 60 days after the last dose of study therapy. Participants of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year without an alternative medical cause
  • Male participants must agree to use an adequate method of contraception starting with the first dose of study therapy through 60 days after the last dose of study therapy
  • Male patients must use a condom during treatment and for 3 months after the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential
  • No other prior invasive malignancy is allowed except for the following: adequately treated basal (or squamous cell) skin cancer, in situ breast or cervical cancer. Stage I or II invasive cancer treated with a curative intent without evidence of disease recurrence for at least five years
  • Individuals must not have known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection prior to trial registration. Those who have completed curative therapy for HCV are eligible. Patients with known human immunodeficiency virus (HIV) infection are eligible if they meet each of the following 3 criteria: * CD4 counts >= 350 mm^3 * Serum HIV viral load of < 25,000 IU/ml and * Treated on a stable antiretroviral regimen

Exclusion Criteria

  • History of previous chemotherapy, or radiation therapy
  • Evidence of metastasis to distant organs (liver, peritoneum, lung, others)
  • Medical co-morbidities that are deemed to make risk of surgery unacceptably high as determined by institutional standards
  • Recent major surgery within 4 weeks prior to starting study treatment. Minor surgery within 2 weeks of starting study treatment. Patients must be recovered from effects of surgery
  • Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's wort) or moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil)
  • Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil)
  • Concomitant use of other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy (hormone replacement therapy is acceptable), radiotherapy (except for palliative), biological therapy or other novel agent) or live virus and live bacterial vaccines while the patient is receiving study medication. Strong or moderate CYP3A inhibitors and inducers should not be taken with study treatment; however, if no other suitable alternative concomitant medication is available, dose reductions may be allowed under careful monitoring
  • Known severe hypersensitivity to cobimetinib or olaparib (or equivalent agents, respectively), or any excipient of these medicinal products, or history of allergic reactions attributed to compounds of similar chemical or biologic composition to cobimetinib or olaparib
  • Clinically significant cardiac disease or impaired cardiac function, including any of the following: * Clinically significant and/or uncontrolled heart disease such as congestive heart failure (New York Heart Association grade >= 2) uncontrolled hypertension, or clinically significant arrhythmia currently requiring medical treatment * Corrected QT using Fridericia's formula (QTcF) > 470 msec for females, or > 450 msec for males, on screening electrocardiogram (ECG) or congenital long QT syndrome * Acute myocardial infarction or unstable angina pectoris < 6 months prior to screening
  • Psychiatric illness/social situations that would limit compliance with study requirements
  • Participants with a history of hypersensitivity reactions to study agents or their excipients
  • Participant is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment

Locations & Contacts

Oregon

Portland
OHSU Knight Cancer Institute
Status: Active
Contact: Charles D. Lopez
Phone: 503-494-8534
Email: lopezc@ohsu.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. Assess the feasibility of collecting tumor tissue for biomarker evaluation prior to and after window therapy with either cobimetinib or olaparib.

SECONDARY OBJECTIVES:

I. Assess preliminary safety and tolerability of cobimetinib.

II. Assess preliminary safety and tolerability of olaparib.

EXPLORATORY OBJECTIVES:

I. Identify predictive biomarkers of sensitivity to cobimetinib or olaparib.

II. Identify emerging mechanism(s) of resistance to cobimetinib or olaparib.

III. Determine cellular and molecular changes in pancreatic tumor cells exposed to cobimetinib or olaparib.

IV. Identify tumor markers suggestive of combinatorial therapy that could overcome resistance to therapy.

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM I: Patients receive cobimetinib orally (PO) once daily (QD) on days 1-10 in the absence of disease progression or unacceptable toxicity. Within 2-5 days, patients undergo surgery.

ARM II: Patients receive olaparib PO twice daily (BID) on days 1-10 in the absence of disease progression or unacceptable toxicity. Within 2-5 days, patients undergo surgery.

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

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
OHSU Knight Cancer Institute

Principal Investigator
Charles D. Lopez

Trial IDs

Primary ID STUDY00019211
Secondary IDs NCI-2019-01265
Clinicaltrials.gov ID NCT04005690