A Phase II Study of Pembrolizumab as Post-Remission Treatment of Patients ≥ 60 With AML

• Sponsor: Michael Boyiadzis (Other)
• Overall Status: Completed
• CT.gov ID: NCT02708641
• Collaborator: Merck Sharp & Dohme LLC (Industry)
• Enrollment: 12
• Location: 1
• Arm: 1
• Actual Duration (Months): 49.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study evaluates the effect of pembrolizumab on the duration of remission in acute myeloid leukemia. Pembrolizumab is given after complete remission is obtained in those with AML at least 60 years old who are not candidates for allogeneic stem cell transplant. The primary purpose of this study is determine if the time to relapse can be extended. Additionally, the safety and tolerability of pembrolizumab will be closely monitored.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: pembrolizumab	Phase 2

Detailed Description

Patients >60 years old with AML often have a dismal prognosis. Even though many of these patients are able to obtain a Complete Response to treatment, relapse occurs in the vast majority of patients. Transplants may reduce relapse rates in this population, but is only feasible in a minority of patients. AML's immunosuppressive microenvironment in general and PD-1/PD-L1 upregulation in particular appears to increase the risk of relapse. Importantly, PD-1 and its ligands are particularly increased after therapy compared to initial diagnosis. As such, PD-1 inhibition with pembrolizumab offers to limit leukemic cell immune escape, thereby allowing the patient's immune system to eradicate the submicroscopic residual disease and reducing relapse rates.

Treatment for this study is 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on simulations performed using the population PK model of Pembrolizumab showing that the fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in the exposure range established in melanoma as associated with maximal efficacy response and 3) will maintain individual patients exposure in the exposure range established in melanoma that are well tolerated and safe.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Pembrolizumab as Post-Remission Treatment of Patients ≥ 60 With Acute Myeloid Leukemia (AML) Who Are Not Transplantation Candidates
• Actual Study Start Date: Oct 4, 2016
• Actual Primary Completion Date: Jun 11, 2020
• Actual Study Completion Date: Dec 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AML patients pembrolizumab 200 mg given IV once every three weeks	Drug: pembrolizumab; 200 mg IV given every three weeks; Other Names: Keytruda

Outcome Measures

Primary Outcome Measures

1. Time to Relapse (TTR) [Up to 24 months]

   Time to recurrence of AML, including only deaths related to recurrence. Relapse of AML is defined as patients reaching remission (bone marrow contains <5% blast cells, blood cell counts return to within normal limits, no signs disease) followed by a return of leukemia cells in the marrow and a decrease in normal blood cells.

2. Worst Grade of Adverse Events Experienced (Unrelated to Relatedness to Study Therapy) [Up to 24 months]

   Worst Grade of AE experienced, regardless of relatedness to study therapy, per CTCAE v5.0.

3. Worst Grade of Adverse Events Experienced (at Least Probably Related to Treatment) [Up to 24 months]

   Worst Grade of AE experienced, at least probably related to treatment, per CTCAE v5.0.

Secondary Outcome Measures

1. Overall Survival (OS) [Up to 48 months]

   The length of time from date of start of treatment that patients are still alive.

Other Outcome Measures

1. Quantification of Activated T Cells [Up to 24 months]

   Determination of activated T cells level (percentages) in peripheral blood. Increased levels of activated T cells may indicate decreasing disease progression.

2. Quantification of Activated NK Cells [Up to 24 months]

   Determination of activated NK cells level (percentages) in peripheral blood. Increased levels of activated T cells may indicate decreasing disease progression.

3. Quantification of Regulatory T Cells (Treg) [Up to 24 months]

   Determination of regulatory T cell (Treg) levels (percentages) in peripheral blood. Treg cells are involved in cancer progression by inhibiting anti-cancer immunity. Increased levels of Treg cells may indicate progressing disease.

4. Cytokine Expression [Up to 24 months]

   Determination of cytokine expression levels (percentages) in peripheral blood. Cytokine expression is associated with cancer progression, immuno-suppression, and decreased anti-cancer response.

5. Granzyme B/Perforin Expression [Up to 24 months]

   Determination of Granzyme B/perforin expression levels (percentages) in peripheral blood. Granzyme B/perforin expression is associated with the suppression of cancer progression.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 60 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• be willing and able to provide written informed consent for the trial

• be ≥ 60 years of age on day of signing informed consent

• have a newly diagnosed AML based on the World Health Organization (WHO) criteria, currently in first complete remission (CR) on a bone marrow biopsy performed within 4 weeks of treatment initiation

• have received the last dose of induction or consolidation chemotherapy within 3 months of treatment initiation

• not be eligible for or willing to proceed with allogeneic stem cell transplant or for whom allogeneic stem cell transplant is not considered standard of care

• have a performance status of ≤ 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale

• demonstrate adequate organ function, with all screening labs performed within 10 days of treatment initiation

• transfusion independent (no red blood cell or platelet transfusions in the preceding 2 weeks of screening)

• negative urine and/or serum pregnancy test

• subjects of reproductive potential must agree to use acceptable birth control method

Exclusion Criteria:

• have a diagnosis of Acute Promyelocytic Leukemia (APL) as defined by the WHO

• currently participating in or has participated in a study of an investigational agent or device within 4 weeks of treatment initiation

• have a diagnosis of immunodeficiency or are receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to treatment initiation

• have prior monoclonal antibody within 4 weeks prior to study Day 1 or have not recovered from adverse events due to agents administered more than 4 weeks earlier

• have prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 have not recovered from adverse events due to previously administered agent(s)

• have a known additional malignancy that is progressing or requires active treatment except for basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy

• have known active central nervous system (CNS) involvement

• have an active autoimmune disease requiring systemic treatment within the past 3 months

• has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis

• have an uncontrolled, life-threatening active infection

• have a history or current evidence of condition, therapy, or laboratory abnormality that would preclude study participation in the opinion of the treating investigator

• have known psychiatric or substance abuse disorders that would interfere with cooperation with the trial requirements

• is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial

• have received prior therapy with any antibody targeting the T-cell co-stimulation or checkpoint pathways

• have a known history of HIV

• have known active Hepatitis B or Hepatitis C

• have received a live vaccine within 30 days prior to treatment initiation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hillman Cancer Center	Pittsburgh	Pennsylvania	United States	15232

Sponsors and Collaborators

• Michael Boyiadzis
• Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Michael Boyiadzis, MD, MHSc, UPMC Hillman Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 3, 2019

More Information

Publications

None provided.

• Responsible Party: Michael Boyiadzis, Associate Professor of Medicine, Division of Hematology Oncology, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT02708641
• Other Study ID Numbers: 15-101
• First Posted: Mar 15, 2016
• Last Update Posted: Aug 10, 2021
• Last Verified: Jul 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Pembrolizumab

Study Results

Participant Flow

Arm/Group Title	Pembro 200 mg - AML Patients
Arm/Group Description	Patients with AML (not transplantation eligible) treated with pembrolizumab 200 mg IV administered once every three weeks, post-remission
Period Title: Overall Study
STARTED	12
COMPLETED	12
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Pembro 200 mg - AML Patients
Arm/Group Description	Patients with AML (not transplantation eligible) treated with pembrolizumab 200 mg IV administered once every three weeks, post-remission
Overall Participants	12
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	70.4
Sex: Female, Male (Count of Participants)
Female	6 50%
Male	6 50%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 8.3%
White	11 91.7%
More than one race	0 0%
Unknown or Not Reported	0 0%
ECOG Performance Status (Count of Participants)
ECOG = 0	4 33.3%
ECOG = 1	8 66.7%

Outcome Measures

1. Primary Outcome

Title	Time to Relapse (TTR)
Description	Time to recurrence of AML, including only deaths related to recurrence. Relapse of AML is defined as patients reaching remission (bone marrow contains <5% blast cells, blood cell counts return to within normal limits, no signs disease) followed by a return of leukemia cells in the marrow and a decrease in normal blood cells.
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

Patients who received at least one cycle of study treatment and were evaluable for response.

Arm/Group Title	Pembro 200 mg - AML Patients
Arm/Group Description	Patients with AML (not transplantation eligible) treated with pembrolizumab 200 mg IV administered once every three weeks, post-remission.
Measure Participants	12
Median (80% Confidence Interval) [months]	12.14

2. Primary Outcome

Title	Worst Grade of Adverse Events Experienced (Unrelated to Relatedness to Study Therapy)
Description	Worst Grade of AE experienced, regardless of relatedness to study therapy, per CTCAE v5.0.
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

Patients who received at least one cycle of study treatment.

Arm/Group Title	Pembro 200 mg - AML Patients
Arm/Group Description	Patients with AML (not transplantation eligible) treated with pembrolizumab 200 mg IV administered once every three weeks, post-remission.
Measure Participants	12
Grade 2	1 8.3%
Grade 3	6 50%
Grade 4	5 41.7%

3. Primary Outcome

Title	Worst Grade of Adverse Events Experienced (at Least Probably Related to Treatment)
Description	Worst Grade of AE experienced, at least probably related to treatment, per CTCAE v5.0.
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

Patients who received at least one cycle of study treatment.

Arm/Group Title	Pembro 200 mg - AML Patients
Arm/Group Description	Patients with AML (not transplantation eligible) treated with pembrolizumab 200 mg IV administered once every three weeks, post-remission.
Measure Participants	12
Grade 2	3 25%
Grade 3	5 41.7%
Grade 4	4 33.3%

4. Primary Outcome

Title	Worst Grade of Adverse Events Experienced (at Least Probably Related to Treatment)
Description	Worst Grade of AE experienced, at least probably related to treatment, per CTCAE v5.0.
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

Patients who received at least one cycle of study treatment.

Arm/Group Title	Pembro 200 mg - AML Patients
Arm/Group Description	Patients with AML (not transplantation eligible) treated with pembrolizumab 200 mg IV administered once every three weeks, post-remission.
Measure Participants	12
Grade 1	3 25%
Grade 2	1 8.3%
Grade 3	1 8.3%
Grade 4	1 8.3%

5. Secondary Outcome

Title	Overall Survival (OS)
Description	The length of time from date of start of treatment that patients are still alive.
Time Frame	Up to 48 months

Outcome Measure Data

Analysis Population Description

Patients eligible for study participation.

Arm/Group Title	Pembro 200 mg - AML Patients
Arm/Group Description	Patients with AML (not transplantation eligible) treated with pembrolizumab 200 mg IV administered once every three weeks, post-remission.
Measure Participants	12
Median (80% Confidence Interval) [months]	42.18

6. Other Pre-specified Outcome

Title	Quantification of Activated T Cells
Description	Determination of activated T cells level (percentages) in peripheral blood. Increased levels of activated T cells may indicate decreasing disease progression.
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

Title	Quantification of Activated NK Cells
Description	Determination of activated NK cells level (percentages) in peripheral blood. Increased levels of activated T cells may indicate decreasing disease progression.
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Other Pre-specified Outcome

Title	Quantification of Regulatory T Cells (Treg)
Description	Determination of regulatory T cell (Treg) levels (percentages) in peripheral blood. Treg cells are involved in cancer progression by inhibiting anti-cancer immunity. Increased levels of Treg cells may indicate progressing disease.
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Other Pre-specified Outcome

Title	Cytokine Expression
Description	Determination of cytokine expression levels (percentages) in peripheral blood. Cytokine expression is associated with cancer progression, immuno-suppression, and decreased anti-cancer response.
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Other Pre-specified Outcome

Title	Granzyme B/Perforin Expression
Description	Determination of Granzyme B/perforin expression levels (percentages) in peripheral blood. Granzyme B/perforin expression is associated with the suppression of cancer progression.
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Adverse Events monitored up to 24 months, All-Cause Mortality monitored up to 48 months
Adverse Event Reporting Description	Adverse Events: Grade 1 and Grade 2 events per CTCAE v4.0 Serious Adverse Events: Grade 3 and Grade 4 events per CTCAE v4.0
Arm/Group Title	AML Patients
Arm/Group Description	pembrolizumab 200 mg given IV once every three weeks
All Cause Mortality
	AML Patients
	Affected / at Risk (%)	# Events
Total	6/12 (50%)
Serious Adverse Events
	AML Patients
	Affected / at Risk (%)	# Events
Total	11/12 (91.7%)
Blood and lymphatic system disorders
Anemia	2/12 (16.7%)
Blood and lymphatic system	1/12 (8.3%)
Febrile neutropenia	1/12 (8.3%)
Cardiac disorders
Cardiac disorders - Other, specify	2/12 (16.7%)
Gastrointestinal disorders
Colitis	2/12 (16.7%)
Diarrhea	2/12 (16.7%)
General disorders
General disorders and admin. site	1/12 (8.3%)
Infections and infestations
Appendicitis	1/12 (8.3%)
Infections and infestations	1/12 (8.3%)
Lung infection	3/12 (25%)
Rhinitis infective	1/12 (8.3%)
Skin infection	1/12 (8.3%)
Urinary tract infection	1/12 (8.3%)
Investigations
Aspartate aminotransferase increased	1/12 (8.3%)
Lymphocyte count decreased	4/12 (33.3%)
Neutrophil count decreased	6/12 (50%)
Platelet count decreased	6/12 (50%)
White blood cell decreased	7/12 (58.3%)
Metabolism and nutrition disorders
Hypocalcemia	1/12 (8.3%)
Hyponatremia	1/12 (8.3%)
Hypophosphatemia	1/12 (8.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms	1/12 (8.3%)
Renal and urinary disorders
Hematuria	1/12 (8.3%)
Vascular disorders
Hypertension	1/12 (8.3%)
Hypotension	2/12 (16.7%)
Other (Not Including Serious) Adverse Events
	AML Patients
	Affected / at Risk (%)	# Events
Total	12/12 (100%)
Blood and lymphatic system disorders
Anemia	7/12 (58.3%)
Cardiac disorders
Acute coronary syndrome	1/12 (8.3%)
Sinus bradycardia	1/12 (8.3%)
Cardiac disorders - Other, specify	3/12 (25%)
Sinus tachycardia	5/12 (41.7%)
Ear and labyrinth disorders
Ear pain	1/12 (8.3%)
Hearing impaired	1/12 (8.3%)
Endocrine disorders
Endocrine disorders - Other, specify	1/12 (8.3%)
Hyperthyroidism	1/12 (8.3%)
Hypothyroidism	2/12 (16.7%)
Eye disorders
Blurred vision	1/12 (8.3%)
Conjunctivitis	1/12 (8.3%)
Floaters	1/12 (8.3%)
Glaucoma	1/12 (8.3%)
Gastrointestinal disorders
Dry mouth	1/12 (8.3%)
Gastroesophageal reflux disease	1/12 (8.3%)
Hemorrhoids	1/12 (8.3%)
Mucositis oral	1/12 (8.3%)
Vomiting	1/12 (8.3%)
Nausea	2/12 (16.7%)
Abdominal pain	3/12 (25%)
Diarrhea	3/12 (25%)
General disorders
Chills	1/12 (8.3%)
General disorders and admin. site	3/12 (25%)
Edema limbs	4/12 (33.3%)
Pain	4/12 (33.3%)
Fever	6/12 (50%)
Fatigue	7/12 (58.3%)
Infections and infestations
Lung infection	1/12 (8.3%)
Rash pustular	1/12 (8.3%)
Scrotal infection	1/12 (8.3%)
Infections and infestations	2/12 (16.7%)
Vaginal infection	2/12 (16.7%)
Injury, poisoning and procedural complications
Bruising	1/12 (8.3%)
Fall	2/12 (16.7%)
Investigations
Alanine aminotransferase increased	1/12 (8.3%)
Alkaline phosphatase increased	1/12 (8.3%)
Cholesterol high	1/12 (8.3%)
Weight loss	1/12 (8.3%)
White blood cell decreased	1/12 (8.3%)
Act. partial thrombop. time prolonged	2/12 (16.7%)
INR increased	2/12 (16.7%)
Investigations - Other, specify	2/12 (16.7%)
Creatinine increased	3/12 (25%)
Neutrophil count decreased	3/12 (25%)
Lymphocyte count decreased	4/12 (33.3%)
Platelet count decreased	4/12 (33.3%)
Metabolism and nutrition disorders
Hypernatremia	1/12 (8.3%)
Hyperuricemia	1/12 (8.3%)
Hypoglycemia	1/12 (8.3%)
Metabolism and nutrition	1/12 (8.3%)
Hypomagnesemia	2/12 (16.7%)
Hyperglycemia	3/12 (25%)
Hyperkalemia	3/12 (25%)
Hypoalbuminemia	3/12 (25%)
Hypokalemia	3/12 (25%)
Anorexia	4/12 (33.3%)
Hypercalcemia	4/12 (33.3%)
Hypophosphatemia	4/12 (33.3%)
Hyponatremia	5/12 (41.7%)
Hypocalcemia	6/12 (50%)
Musculoskeletal and connective tissue disorders
Chest wall pain	1/12 (8.3%)
Generalized muscle weakness	1/12 (8.3%)
Arthralgia	2/12 (16.7%)
Myalgia	2/12 (16.7%)
Pain in extremity	2/12 (16.7%)
Musculoskeletal and connective tissue	3/12 (25%)
Nervous system disorders
Dizziness	2/12 (16.7%)
Headache	2/12 (16.7%)
Psychiatric disorders
Anxiety	1/12 (8.3%)
Confusion	1/12 (8.3%)
Insomnia	2/12 (16.7%)
Renal and urinary disorders
Cystitis noninfective	1/12 (8.3%)
Hematuria	1/12 (8.3%)
Hemoglobinuria	1/12 (8.3%)
Urinary incontinence	1/12 (8.3%)
Reproductive system and breast disorders
Scrotal pain	1/12 (8.3%)
Vaginal discharge	1/12 (8.3%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	1/12 (8.3%)
Sinus disorder	1/12 (8.3%)
Dyspnea	2/12 (16.7%)
Postnasal drip	2/12 (16.7%)
Nasal congestion	3/12 (25%)
Sore throat	3/12 (25%)
Cough	8/12 (66.7%)
Skin and subcutaneous tissue disorders
Dry skin	2/12 (16.7%)
Pruritus	2/12 (16.7%)
Skin and subcut. tissue	3/12 (25%)
Vascular disorders
Hypertension	3/12 (25%)
Hypotension	3/12 (25%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.