A Phase 2 Study of Pembrolizumab (MK-3475) in Combination With Azacitidine in Subjects With Chemo-refractory Metastatic Colorectal Cancer

NCT02260440 | Completed Phase 2 Results DMC

• 1 other identifier: 14-118
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open label, single-arm, Phase 2 trial to evaluate the anti-tumor activity, safety, and tolerability of Pembrolizumab in combination with azacitidine in subjects with chemo-refractory mCRC without any further standard treatment options Dosage and regimen for all study periods

• Pembrolizumab will be given at 200 mg every 21 days.
• Azacitidine will be given at 100 mg daily subcutaneous injection on days 1-5 every 21 days. The first assessment of tumor response will be performed after cycle 3 (9 weeks), and thereafter approximately every 9 weeks, every 3 cycles of therapy. The modified RECIST 1.1 will be used to establish disease response or progression. All patients will be evaluated and graded for adverse events according to the NCI Common Terminology for Adverse Events, version 4.0 (NCI-CTCAE).

Conditions

Metastatic Colorectal Cancer

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate (ORR)

  The objective response rate is estimated by the proportion (percentage) of participants with the best response of complete response (CR), or partial response (PR) by RECIST 1.1 criteria, with corresponding exact 95% confidence limits being reported. Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

  Up to 14 months

Secondary Outcomes (2)

• Progression-free Survival (PFS)

  Up to 2 years

• Overall Survival (OS)

  Up to 2 years

Study Arms (1)

Pembrolizumab and Azacitidine Arm

EXPERIMENTAL

9 cycles * Pembrolizumab will be given at 200 mg every 21 days. * Azacitidine will be given at 100 mg daily subcutaneous injection on days 1-5 every 21 days.

Drug: Pembrolizumab; Drug: Azacitidine

Interventions

Pembrolizumab DRUG

Pembrolizumab will be given at 200 mg every 21 days

Pembrolizumab and Azacitidine Arm

Azacitidine DRUG

Azacitidine will be given at 100 mg daily subcutaneous injection on days 1-5 every 21 days.

Pembrolizumab and Azacitidine Arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Be willing and able to provide written informed consent/assent for the trial.
• Be 18 years of age or older on day of signing informed consent.
• The diagnosis of mCRC will be based on histologic or cytologic confirmation.
• Have mCRC that has been previously treated with currently approved standard therapies.
• Have measurable disease based on RECIST 1.1.
• At least 1 of the tumor sites must be amenable to core needle biopsy and this may not be the site of disease used to measure antitumor response. Patient must agree to this mandatory biopsy.
• Have a performance status of 0 or 1 on the ECOG Performance Scale.
• Demonstrate adequate organ function, all screening labs should be performed within 14 days of treatment initiation.
• 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 \> 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.

You may not qualify if:

• 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.
• Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ 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 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
• \- Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
• 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 extensive metastatic tumor burden in the liver with serum albumin \<3.0 g/dL.
• Has known renal tubular acidosis with serum bicarbonate \<20 mEq/L.
• Has a known hypersensitivity to azacitidine or mannitol.
• 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 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 evidence of interstitial lung disease or active, non-infectious pneumonitis.
• 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.

Sponsors & Collaborators

• Anuradha Krishnamurthy: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

Location

Related Publications (1)

• Kuang C, Park Y, Augustin RC, Lin Y, Hartman DJ, Seigh L, Pai RK, Sun W, Bahary N, Ohr J, Rhee JC, Marks SM, Beasley HS, Shuai Y, Herman JG, Zarour HM, Chu E, Lee JJ, Krishnamurthy A. Pembrolizumab plus azacitidine in patients with chemotherapy refractory metastatic colorectal cancer: a single-arm phase 2 trial and correlative biomarker analysis. Clin Epigenetics. 2022 Jan 6;14(1):3. doi: 10.1186/s13148-021-01226-y.

  PMID: 34991708 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

pembrolizumab; Azacitidine

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Results Point of Contact

• Title: Anuradha Krishnamurthy, MD
• Organization: UPMC Hillman Cancer Center

krishnamurthya2@upmc.edu

412-623-3283

Study Officials

• Anuradha Krishnamurthy, MD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: October 6, 2014
• First Posted: October 9, 2014
• Study Start: January 1, 2015
• Primary Completion: March 1, 2016
• Study Completion: September 1, 2017
• Last Updated: September 17, 2019
• Results First Posted: May 16, 2017

Record last verified: 2019-09

Locations

US (1)