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

• ClinicalTrials.gov Identifier: NCT02260440
• Recruitment Status: Completed
• First Posted: October 9, 2014
• Results First Posted: May 16, 2017
• Last Update Posted: September 17, 2019
• Sponsor: Anuradha Krishnamurthy
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Anuradha Krishnamurthy, University of Pittsburgh

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Metastatic Colorectal Cancer
• Interventions: Drug: Pembrolizumab; Drug: Azacitidine
• Enrollment: 31

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Pembrolizumab and Azacitidine
Arm/Group Description	200 mg of Pembrolizumab was administered intravenously over 30 minutes on Day 1 of every 21 day cycle. 100 mg of Azacitidine was given daily via subcutaneous injection on days 1-5 every 21 days. Treatment continued for 9 cycles (about 27 weeks) or until there was an evidence of progression of disease (PD) or unacceptable toxicity before the completion of the planned 9 cycles.
Period Title: Overall Study
Started	31
Completed	31
Not Completed	0

Baseline Characteristics

Arm/Group Title		Pembrolizumab and Azacitidine
Arm/Group Description		200 mg of Pembrolizumab was administered intravenously over 30 minutes on Day 1 of every 21 day cycle. 100 mg of Azacitidine was given daily via subcutaneous injection on days 1-5 every 21 days. Treatment continued for 9 cycles (about 27 weeks) or until there was an evidence of progression of disease (PD) or unacceptable toxicity before the completion of the planned 9 cycles.
Overall Number of Baseline Participants		31
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Median (Full Range); Unit of measure: Years
	Number Analyzed	31 participants
		61; (30 to 79)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	31 participants
	Female	14 45.2%
	Male	17 54.8%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate (ORR)
Description	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.
Time Frame	Up to 14 months

Outcome Measure Data

Analysis Population Description

Participants who received at least one dose of study therapy (median, 3 cycles; range, 1-8).

Arm/Group Title	Pembrolizumab and Azacitidine
Arm/Group Description:	200 mg of Pembrolizumab was administered intravenously over 30 minutes on Day 1 of every 21 day cycle. 100 mg of Azacitidine was given daily via subcutaneous injection on days 1-5 every 21 days. Treatment continued for 9 cycles (about 27 weeks) or until there was an evidence of progression of disease (PD) or unacceptable toxicity before the completion of the planned 9 cycles.
Overall Number of Participants Analyzed	30
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	3; (1 to 17)

2. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	Progression-free Survival (PFS) (median) was determined using the number of months measured from the initial date of treatment to the date of documented progression, or the date of death (in the absence of progression) of participants. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Participants who received at least one dose of study therapy (median, 3 cycles; range, 1-8).

Arm/Group Title	Pembrolizumab and Azacitidine
Arm/Group Description:	200 mg of Pembrolizumab was administered intravenously over 30 minutes on Day 1 of every 21 day cycle. 100 mg of Azacitidine was given daily via subcutaneous injection on days 1-5 every 21 days. Treatment continued for 9 cycles (about 27 weeks) or until there was an evidence of progression of disease (PD) or unacceptable toxicity before the completion of the planned 9 cycles.
Overall Number of Participants Analyzed	30
Median (95% Confidence Interval); Unit of Measure: months
	2.1; (1.8 to 2.8)

3. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall Survival (OS) (median) was determined using the number of months measured from the initial date of treatment to the recorded date of death of participants.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Participants who received at least one dose of study therapy (median, 3 cycles; range, 1-8).

Arm/Group Title	Pembrolizumab and Azacitidine
Arm/Group Description:	200 mg of Pembrolizumab was administered intravenously over 30 minutes on Day 1 of every 21 day cycle. 100 mg of Azacitidine was given daily via subcutaneous injection on days 1-5 every 21 days. Treatment continued for 9 cycles (about 27 weeks) or until there was an evidence of progression of disease (PD) or unacceptable toxicity before the completion of the planned 9 cycles.
Overall Number of Participants Analyzed	30
Median (95% Confidence Interval); Unit of Measure: months
	6.2; (3.5 to 8.7)

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Pembrolizumab and Azacitidine
Arm/Group Description	200 mg of Pembrolizumab was administered intravenously over 30 minutes on Day 1 of every 21 day cycle. 100 mg of Azacitidine was given daily via subcutaneous injection on days 1-5 every 21 days. Treatment continued for 9 cycles (about 27 weeks) or until there was an evidence of progression of disease (PD) or unacceptable toxicity before the completion of the planned 9 cycles.
All-Cause Mortality
	Pembrolizumab and Azacitidine
	Affected / at Risk (%)
Total	--/--
Serious Adverse Events
	Pembrolizumab and Azacitidine
	Affected / at Risk (%)
Total	13/30 (43.33%)
Blood and lymphatic system disorders
Anemia †	1/30 (3.33%)
Cardiac disorders
Sinus tachycardia †	1/30 (3.33%)
Gastrointestinal disorders
Abdominal distension †	2/30 (6.67%)
General disorders
Death NOS †	1/30 (3.33%)
Fatigue †	1/30 (3.33%)
Hepatobiliary disorders
Hepatobiliary disorders - Other, specify †	1/30 (3.33%)
Infections and infestations
Rash pustular †	1/30 (3.33%)
Investigations
Alanine aminotransferase increased †	1/30 (3.33%)
Blood bilirubin increased †	1/30 (3.33%)
Metabolism and nutrition disorders
Dehydration †	1/30 (3.33%)
Hyponatremia †	1/30 (3.33%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness †	1/30 (3.33%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify †	3/30 (10.00%)
Nervous system disorders
Lethargy †	1/30 (3.33%)
Stroke †	1/30 (3.33%)
Psychiatric disorders
Confusion †	1/30 (3.33%)
Renal and urinary disorders
Acute kidney injury †	1/30 (3.33%)
Hematuria †	1/30 (3.33%)
Renal and urinary disorders - Other, specify †	1/30 (3.33%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion †	1/30 (3.33%)
† Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Pembrolizumab and Azacitidine
	Affected / at Risk (%)
Total	30/30 (100.00%)
Blood and lymphatic system disorders
Anemia †	18/30 (60.00%)
Cardiac disorders
Sinus bradycardia †	3/30 (10.00%)
Gastrointestinal disorders
Diarrhea †	2/30 (6.67%)
Gastrointestinal disorders - Other, specify †	3/30 (10.00%)
Vomiting †	3/30 (10.00%)
Abdominal pain †	4/30 (13.33%)
Constipation †	7/30 (23.33%)
Nausea †	9/30 (30.00%)
General disorders
Fever †	2/30 (6.67%)
General disorders and administration site conditions - Other, specify †	3/30 (10.00%)
Pain †	3/30 (10.00%)
Fatigue †	12/30 (40.00%)
Investigations
Creatinine increased †	4/30 (13.33%)
Neutrophil count decreased †	4/30 (13.33%)
Platelet count decreased †	4/30 (13.33%)
Blood bilirubin increased †	5/30 (16.67%)
White blood cell decreased †	7/30 (23.33%)
Alanine aminotransferase increased †	9/30 (30.00%)
Lymphocyte count decreased †	9/30 (30.00%)
Aspartate aminotransferase increased †	11/30 (36.67%)
Alkaline phosphatase increased †	14/30 (46.67%)
Metabolism and nutrition disorders
Anorexia †	2/30 (6.67%)
Hypokalemia †	2/30 (6.67%)
Hypophosphatemia †	2/30 (6.67%)
Metabolism and nutrition disorders - Other, specify †	3/30 (10.00%)
Hyperkalemia †	4/30 (13.33%)
Hypernatremia †	4/30 (13.33%)
Hypocalcemia †	7/30 (23.33%)
Hyponatremia †	16/30 (53.33%)
Hypoalbuminemia †	18/30 (60.00%)
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorder - Other, specify †	2/30 (6.67%)
Nervous system disorders
Headache †	2/30 (6.67%)
Psychiatric disorders
Anxiety †	2/30 (6.67%)
Respiratory, thoracic and mediastinal disorders
Hypoxia †	2/30 (6.67%)
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders - Other, specify †	3/30 (10.00%)
† Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Anuradha Krishnamurthy, MD
• Organization: UPMC Hillman Cancer Center
• Phone: 412-623-3283
• EMail: krishnamurthya2@upmc.edu

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Anuradha Krishnamurthy, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT02260440
• Other Study ID Numbers: 14-118
• First Submitted: October 6, 2014
• First Posted: October 9, 2014
• Results First Submitted: April 10, 2017
• Results First Posted: May 16, 2017
• Last Update Posted: September 17, 2019