Overview

Phase I Study MK-3475 With Chemotherapy in Patients With Advanced GI Cancers

Status:
Terminated
Trial end date:
2017-06-26
Target enrollment:
0
Participant gender:
All
Summary
This is a Phase I dose escalation trial to assess MTD of MK-3475 in combination with mFOLFOX6 followed by a safety expansion open label, nonrandomized trial with MK-3475 at MTD in combination with mFOLFOX6 and supplemental celecoxib in 4 cohorts of advanced/metastatic GI malignancies (pancreatic, gastro esophageal, colorectal/appendiceal adenocarcinoma and biliary carcinoma) to assess response rate, clinical benefit rate, progression free survival and overall survival. The safety expansion cohort will assess the effect of the addition of celecoxib to patients that do not respond to combination MK-3475/mFOLFOX treatment.
Phase:
Phase 1
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
University of Utah
Collaborator:
Merck Sharp & Dohme Corp.
Treatments:
Pembrolizumab
Criteria
Inclusion Criteria:

- Phase I: Patients with any locally advanced or metastatic gastrointestinal malignancy
which mFOLFOX6 is indicated for treatment

- Safety expansion: Patients with one of the following locally advanced unresectable or
metastatic pathologically confirmed diagnosis: Colorectal Carcinoma and Appendiceal
Adenocarcinoma, Gastro-Esophageal -Carcinoma Note: esophageal squamous cell carcinoma
is exclusionary, Biliary -Tract Carcinoma Note: Hepatocellular carcinoma is excluded,
Pancreatic Carcinoma

- Patients must be willing to provide and have available formalin fixed paraffin
embedded tissue sample from archival tissue or newly obtained core or excisional
biopsy of a tumor lesion for central analysis. Note: Fine Needle Aspiration's (FNA),
frozen samples, plastic embedded samples, cell blocks, clots, bone, bone marrow, or
cytologic specimens are exclusionary

- Patients must have measurable disease based on irRECIST (Safety expansion only)

- Patients must be 18 years of age on day of signing informed consent

- Have a performance status of 0 or 1 on the ECOG Performance Scale

- Patients must demonstrate adequate organ function as based on screening labs performed
within 14 days of treatment initiation

- Patients are allowed to have received prior treatment with mFOLFOX6. If patients are
currently receiving treatment with mFOLFOX6, the subject must have documented disease
progression. Patients must also be able to tolerate standard mFOLFOX6. Reduced dosing
of mFOLFOX6 at enrollment is exclusionary.

- Patients must be able to provide informed consent and willing to sign an approved
consent form that conforms to federal and institutional guidelines

- Female subject of childbearing potential should have a negative urine or serum
pregnancy 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 subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 120 days after the last dose of study medication Subjects of
childbearing potential are those who have not been surgically sterilized or have not
been free from menses for greater than 1 year

- Male subjects should agree to use an adequate method of contraception starting with
the first dose of study therapy through 120 days after the last dose of study therapy

Exclusion Criteria:

- Is currently participating in or has participated in a study of an investigational
agent or using an investigational device within 4 weeks of the first dose of treatment

- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment. Note: Dexamethasone prior to treatment on day 1 of each treatment cycle is
allowed

- Subjects with greater than or equal to Grade 2 neuropathy

- Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not
recovered (i.e., greater than or equal to Grade 1 or at baseline) from adverse events
due to agents administered more than 4 weeks earlier

- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study Day 1 or who has not recovered (i.e., less than or equal
to Grade 1 or at baseline) from adverse events due to a previously administered agent.
Note: If subject received major surgery, they must have recovered adequately from the
toxicity and/or complications from the intervention prior to starting therapy

- History of greater than or equal to grade 3 allergic reaction to mFOLFOX6 (patients
successfully desensitized to oxaliplatin are eligible or those willing to undergo
desensitization during the first two cycles of mFOLFOX6 per institutional guidelines)

- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, or in situ cervical cancer that has undergone potentially curative therapy

- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four weeks
prior to the first dose of trial treatment and any neurologic symptoms have returned
to baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment

- Has an active autoimmune disease requiring systemic treatment within the past 3 months
or a documented history of clinically severe autoimmune disease, or a syndrome that
requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or
resolved childhood asthma/atopy would be an exception to this rule. Subjects that
require intermittent use of bronchodilators, topical steroids or local steroid
injections would not be excluded from the study. Subjects with hypothyroidism stable
on hormone replacement or Sjorgen's syndrome will not be excluded from the study

- Has history of interstitial lung disease or active, non-infectious pneumonitis
requiring steroids.

- Has an active infection requiring systemic therapy

- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator

- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial

- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment

- Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation
or checkpoint pathways)

- Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). Note:
testing not required at baseline unless clinically indicated

- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected). Note: testing not required at baseline for unless
clinically indicated

- Has received a live vaccine within 30 days prior to the first dose of trial treatment

- Patients are ineligible if they plan on regular use of NSAIDs at any dose more than 2
times per week (on average) or aspirin at more than 325 mg at least three times per
week, on average. Low-dose aspirin not exceeding 100mg/day is permitted. Patients who
agree to stop regular NSAIDS or higher dose aspirin are eligible and no wash out
period is required.

- The patient has significant bleeding disorders or vasculitis. History of significant
(in the opinion of the investigator) upper gastrointestinal ulceration, upper
gastrointestinal bleeding, or upper gastrointestinal perforation within the past 3
years. Patients with a history of ulceration, bleeding or perforation in the lower
bowel are not excluded.

- Prior allergic reaction or hypersensitivity to sulfonamides (may be allowed per
investigator discretion based on patient history), celecoxib or NSAIDs.

- Cardiac risk factors including: 1) Uncontrolled high blood pressure (systolic blood
pressure greater than 150); 2) Unstable angina; 3) History of documented myocardial
infarction or cerebrovascular accident; 4 New York Heart Association class III or IV
heart failure.