Clinical Trials /

Targeted PARP or MEK/ERK Inhibition in Patients With Pancreatic Cancer

NCT04005690

Description:

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

Related Conditions:
  • Pancreatic Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Cobimetinib or Olaparib in Treating Patients With Resectable Pancreatic Cancer
  • Official Title: A Feasibility Study to Assess a Window of Opportunity Strategy for Targeted PARP or MEK Inhibition in Patients With Pancreatic Ductal Adenocarcinoma

Clinical Trial IDs

  • ORG STUDY ID: STUDY00019211
  • SECONDARY ID: NCI-2019-01265
  • SECONDARY ID: STUDY00019211
  • SECONDARY ID: P30CA069533
  • NCT ID: NCT04005690

Conditions

  • Resectable Pancreatic Ductal Adenocarcinoma
  • Stage 0 Pancreatic Cancer AJCC v8
  • Stage I Pancreatic Cancer AJCC v8
  • Stage IA Pancreatic Cancer AJCC v8
  • Stage IB Pancreatic Cancer AJCC v8
  • Stage II Pancreatic Cancer AJCC v8
  • Stage IIA Pancreatic Cancer AJCC v8
  • Stage IIB Pancreatic Cancer AJCC v8
  • Stage III Pancreatic Cancer AJCC v8

Interventions

DrugSynonymsArms
CobimetinibCotellic, GDC-0973, MEK Inhibitor GDC-0973, XL518Arm I (cobimetinib)
OlaparibAZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281Arm II (olaparib)

Purpose

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 plus olaparib will work better than standard treatments in patients with pancreatic cancer.

Detailed Description

      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 12-24 hours, 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 12-24 hours, patients undergo surgery.

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

Trial Arms

NameTypeDescriptionInterventions
Arm I (cobimetinib)ExperimentalPatients receive cobimetinib PO QD on days 1-10 in the absence of disease progression or unacceptable toxicity. Within 2-5 days, patients undergo surgery.
  • Cobimetinib
Arm II (olaparib)ExperimentalPatients receive olaparib PO BID on days 1-10 in the absence of disease progression or unacceptable toxicity. Within 2-5 days, patients undergo surgery.
  • Olaparib

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
      
Maximum Eligible Age:78 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of subjects that complete window treatment with cobimetinib or olaparib, and undergo collection of both pre-treatment and post-treatment tumor tissue samples
Time Frame:At completion of surgery, up to 15 days
Safety Issue:
Description:Will be estimated with a 95% confidence interval (CI).

Secondary Outcome Measures

Measure:Incidence of >= grade 3 toxicities for the cobimetinib window therapy
Time Frame:Up to 30 days
Safety Issue:
Description:Assessed per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The 95% CI will be reported with the point estimate of toxicity rate. All grade 3+ acute toxicities will also be summarized with its grade.
Measure:Incidence of >= grade 3 toxicities for the olaparib window therapy
Time Frame:Up to 30 days
Safety Issue:
Description:Assessed per CTCAE version 5.0. The 95% CI will be reported with the point estimate of toxicity rate. All grade 3+ acute toxicities will also be summarized with its grade.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:OHSU Knight Cancer Institute

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