1454GCC: Anti-PD-1 (MK-3475) and IMiD (Pomalidomide) Combination Immunotherapy in Relapsed/Refractory Multiple Myeloma

• Sponsor: Ashraf Badros (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02289222
• Collaborator: Merck Sharp & Dohme LLC (Industry)
• Enrollment: 48
• Location: 1
• Arm: 1
• Actual Duration (Months): 31.2
• Patients Per Site Per Month: 1.5

Study Details

Study Description

Brief Summary

This is an open label trial of Anti PD1/MD-3475, Pomalidomide and dexamethasone. The study will use standard (FDA approved) doses for both pomalidomide and dexamethasone. The experimental drug Anti PD-1 (MK 3475) given on days 1 and 14.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: MK-3475; Drug: Pomalidomide; Drug: Dexamethasone	Phase 1/Phase 2

Detailed Description

This phase I/II study is focused on patients with relapsed or refractory multiple myeloma. MK-3475 will be given as an intravenous infusion at every 2 weeks. Treatment will be administered on an outpatient basis.

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 1454GCC: Phase I/II Anti-PD-1 (MK-3475) and IMiD (Pomalidomide) Combination Immunotherapy in Relapsed/Refractory Multiple Myeloma
• Actual Study Start Date: Dec 30, 2014
• Actual Primary Completion Date: Aug 7, 2017
• Actual Study Completion Date: Aug 7, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pomalidomide, Dexamethasone & MK-3475 Pomalidomide is given at standard dose of 4 mg daily orally for 21 days and dexamethasone is given at 40 mg orally weekly. MK3475 will be given as an intravenous infusion at 200 mg every 2 weeks (days 1 and 14).	Drug: MK-3475; Anti PD-1 (MD 3475) will be given as an intravenous infusion at 200 mg every 2 weeks.; Other Names: Generic name: Pembrolizumab - Trade name: Keytruda ; Drug: Pomalidomide; Pomalidomide is given at standard dose of 4 mg daily orally for 21 days; Other Names: Pomalyst, CC-4047, Actimid ; Drug: Dexamethasone; Dexamethasone is given at 40 mg orally weekly; Other Names: Decadron

Outcome Measures

Primary Outcome Measures

1. The Number of Participants With Adverse Events [24 month]

   Establish the safety and tolerability of Pomalidomide and Dexamethasone in combination with MK-3475

Secondary Outcome Measures

1. PD-LI Expression On Myeloma Cells [Tissue sample collection will take place before starting study therapy with MK-3475 at baseline and again at time of relapse as defined by the International Myeloma Working Group Response Criteria (Average of up to 24months)]

   The identification of a biomarker for response by evaluating PD-1/PDL-1 expression in patients' bone marrow aspirate samples will be analyzed in order to help select patients for future anti-PD-1 therapy. The main exploratory biomarker analysis was to examine potential correlation between expression of PD-1 on T cells and PD-L1 on myeloma cells with clinical outcome using the following parameters: response rate focusing on responses ≥ very good partial response (VGPR) and PFS. SAS software (v.9.4; SAS Institute, Inc, Cary, NC) was used for statistical analyses.

2. Time to Progression Free Survival (PFS) [PFS assessments will take place after starting study therapy with MD-3475 and will continue until the start of a new anti-neoplastic therapy, disease progression, death, or the end of study up to an average of 24 months.]

   PFS will be measured in all participants. Survival and PFS functions were estimated using the Kaplan-Meier method. The Cox regression model was used to assess the following plausible risk factors for OS and PFS: age, isotype, number of cycles of therapy, and cytogenetic profile.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Confirmed diagnosis of relapsed and/or refractory MM according to International Myeloma Working Group guidelines (2003)

2. Received two lines of prior therapy that includes an IMiD (lenalidomide or thalidomide) and a proteasome inhibitor (bortezomib and/or carfilzomib) (used either separately or in combination). (a). Prior pomalidomide therapy is permitted, provided the patient achieved at least a partial remission and had not progressed for 3 months after stopping therapy.

3. Measureable disease as defined by the protocol (assessed within 28 days prior to registration).

4. Be willing and able to provide written informed consent/assent for the trial.

5. Be over 18 years of age on day of signing informed consent.

6. Have a performance status of 2 on the ECOG Performance Scale.

7. Demonstrate adequate organ function as defined by the protocol.

8. Female subject of childbearing potential should have a negative serum pregnancy within 72 hours prior to receiving the first dose of study drug.

9. Male subjects should agree to use an adequate method of contraception.

Exclusion Criteria:

1. 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.

2. Has a diagnosis of immunodeficiency (HIV) or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.

3. 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.

4. 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., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. (Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.)

5. 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 situ cervical cancer that has undergone potentially curative therapy.

6. Has known active central nervous system disease and/or carcinomatous meningitis.

7. 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.

8. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.

9. Has an active infection requiring systemic therapy.

10. Has a history or current evidence of any condition, therapy, or lab 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.

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

12. Pregnant or breastfeeding, or expecting to conceive or father children during study participation.

13. 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 as per the protocol.

14. has known active Hepatitis B or Hepatitis C.

15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Greenebaum Cancer Center at University of Maryland Medical Center	Baltimore	Maryland	United States	21201-1592

Sponsors and Collaborators

• Ashraf Badros
• Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Ashraf Z Badros, M.B.,Ch.B, University of Maryland Greenebaum Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 7, 2017

More Information

Publications

None provided.

• Responsible Party: Ashraf Badros, Sponsor-Investigator, University of Maryland, Baltimore
• ClinicalTrials.gov Identifier: NCT02289222
• Other Study ID Numbers: HP-00061522; GCC1454
• First Posted: Nov 13, 2014
• Last Update Posted: Nov 5, 2019
• Last Verified: Nov 1, 2019

• Keywords provided by Ashraf Badros, Sponsor-Investigator, University of Maryland, Baltimore: Relapsed/Refractory; MK-3475 & Pomalidomide; Immunotherapy
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Dexamethasone; Pembrolizumab; Pomalidomide

Study Results

Participant Flow

Recruitment Details	Participants were recruited from the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center between December 2014 and May 2016.

Arm/Group Title	Pomalidomide, Dexamethasone & MK-3475
Arm/Group Description	Pomalidomide is given at standard dose of 4 mg daily orally for 21 days and dexamethasone is given at 40 mg orally weekly. MK3475 will be given as an intravenous infusion at 200 mg every 2 weeks (days 1 and 14). MK-3475: Anti PD-1 (MD 3475) will be given as an intravenous infusion at 200 mg every 2 weeks. Pomalidomide: Pomalidomide is given at standard dose of 4 mg daily orally for 21 days Dexamethasone: Dexamethasone is given at 40 mg orally weekly
Period Title: Overall Study
STARTED	48
COMPLETED	48
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Pomalidomide, Dexamethasone & MK-3475
Arm/Group Description	Pomalidomide is given at standard dose of 4 mg daily orally for 21 days and dexamethasone is given at 40 mg orally weekly. MK3475 will be given as an intravenous infusion at 200 mg every 2 weeks (days 1 and 14). MK-3475: Anti PD-1 (MD 3475) will be given as an intravenous infusion at 200 mg every 2 weeks. Pomalidomide: Pomalidomide is given at standard dose of 4 mg daily orally for 21 days Dexamethasone: Dexamethasone is given at 40 mg orally weekly
Overall Participants	48
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64
Sex: Female, Male (Count of Participants)
Female	16 33.3%
Male	32 66.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	46 95.8%
Unknown or Not Reported	2 4.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 4.2%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	18 37.5%
White	26 54.2%
More than one race	0 0%
Unknown or Not Reported	2 4.2%

Outcome Measures

1. Primary Outcome

Title	The Number of Participants With Adverse Events
Description	Establish the safety and tolerability of Pomalidomide and Dexamethasone in combination with MK-3475
Time Frame	24 month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pomalidomide, Dexamethasone & MK-3475
Arm/Group Description	Pomalidomide is given at standard dose of 4 mg daily orally for 21 days and dexamethasone is given at 40 mg orally weekly. MK3475 will be given as an intravenous infusion at 200 mg every 2 weeks (days 1 and 14). MK-3475: Anti PD-1 (MD 3475) will be given as an intravenous infusion at 200 mg every 2 weeks. Pomalidomide: Pomalidomide is given at standard dose of 4 mg daily orally for 21 days Dexamethasone: Dexamethasone is given at 40 mg orally weekly
Measure Participants	48
Count of Participants [Participants]	48 100%

2. Secondary Outcome

Title	PD-LI Expression On Myeloma Cells
Description	The identification of a biomarker for response by evaluating PD-1/PDL-1 expression in patients' bone marrow aspirate samples will be analyzed in order to help select patients for future anti-PD-1 therapy. The main exploratory biomarker analysis was to examine potential correlation between expression of PD-1 on T cells and PD-L1 on myeloma cells with clinical outcome using the following parameters: response rate focusing on responses ≥ very good partial response (VGPR) and PFS. SAS software (v.9.4; SAS Institute, Inc, Cary, NC) was used for statistical analyses.
Time Frame	Tissue sample collection will take place before starting study therapy with MK-3475 at baseline and again at time of relapse as defined by the International Myeloma Working Group Response Criteria (Average of up to 24months)

Outcome Measure Data

Analysis Population Description

Data were analyzed for 29 samples.

Arm/Group Title	Pomalidomide, Dexamethasone & MK-3475
Arm/Group Description	Pomalidomide is given at standard dose of 4 mg daily orally for 21 days and dexamethasone is given at 40 mg orally weekly. MK3475 will be given as an intravenous infusion at 200 mg every 2 weeks (days 1 and 14). MK-3475: Anti PD-1 (MD 3475) will be given as an intravenous infusion at 200 mg every 2 weeks. Pomalidomide: Pomalidomide is given at standard dose of 4 mg daily orally for 21 days Dexamethasone: Dexamethasone is given at 40 mg orally weekly
Measure Participants	29
Negative	10 20.8%
Weak Positive	6 12.5%
Positive	13 27.1%

3. Secondary Outcome

Title	Time to Progression Free Survival (PFS)
Description	PFS will be measured in all participants. Survival and PFS functions were estimated using the Kaplan-Meier method. The Cox regression model was used to assess the following plausible risk factors for OS and PFS: age, isotype, number of cycles of therapy, and cytogenetic profile.
Time Frame	PFS assessments will take place after starting study therapy with MD-3475 and will continue until the start of a new anti-neoplastic therapy, disease progression, death, or the end of study up to an average of 24 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pomalidomide, Dexamethasone & MK-3475
Arm/Group Description	Pomalidomide is given at standard dose of 4 mg daily orally for 21 days and dexamethasone is given at 40 mg orally weekly. MK3475 will be given as an intravenous infusion at 200 mg every 2 weeks (days 1 and 14). MK-3475: Anti PD-1 (MD 3475) will be given as an intravenous infusion at 200 mg every 2 weeks. Pomalidomide: Pomalidomide is given at standard dose of 4 mg daily orally for 21 days Dexamethasone: Dexamethasone is given at 40 mg orally weekly
Measure Participants	48
Median (95% Confidence Interval) [Months]	17.4

Adverse Events

Time Frame	Reported Adverse Events (AEs) include events starting on or after Day 0 and up to 30 days of receiving the last dose of study medication.
Arm/Group Title	Pomalidomide, Dexamethasone & MK-3475
Arm/Group Description	Pomalidomide is given at standard dose of 4 mg daily orally for 21 days and dexamethasone is given at 40 mg orally weekly. MK3475 will be given as an intravenous infusion at 200 mg every 2 weeks (days 1 and 14). MK-3475: Anti PD-1 (MD 3475) will be given as an intravenous infusion at 200 mg every 2 weeks. Pomalidomide: Pomalidomide is given at standard dose of 4 mg daily orally for 21 days Dexamethasone: Dexamethasone is given at 40 mg orally weekly
All Cause Mortality
	Pomalidomide, Dexamethasone & MK-3475
	Affected / at Risk (%)	# Events
Total	2/48 (4.2%)
Serious Adverse Events
	Pomalidomide, Dexamethasone & MK-3475
	Affected / at Risk (%)	# Events
Total	27/48 (56.3%)
Cardiac disorders
acute coronary syndrome	1/48 (2.1%)
heart failure	1/48 (2.1%)
cardiac arrest	1/48 (2.1%)
Endocrine disorders
adrenal insufficiency	1/48 (2.1%)
Gastrointestinal disorders
colitis	1/48 (2.1%)
lower gastrointestinal hemorrhage	1/48 (2.1%)
General disorders
fever	2/48 (4.2%)
Infections and infestations
other, bacteremia	1/48 (2.1%)
skin infection	1/48 (2.1%)
Injury, poisoning and procedural complications
fracture	1/48 (2.1%)
hip fracture	1/48 (2.1%)
Investigations
alanine aminotransferase increased	1/48 (2.1%)
alkaline phosphatase increased	1/48 (2.1%)
creatinine increased	1/48 (2.1%)
Metabolism and nutrition disorders
hyponatremia	1/48 (2.1%)
Musculoskeletal and connective tissue disorders
other, meniscus tear	1/48 (2.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
other, breast cancer	1/48 (2.1%)
Nervous system disorders
intracranial hemorrhage	2/48 (4.2%)
syncope	1/48 (2.1%)
Renal and urinary disorders
urinary retention	1/48 (2.1%)
Respiratory, thoracic and mediastinal disorders
bronchitis	1/48 (2.1%)
dyspnea	2/48 (4.2%)
lung infection	9/48 (18.8%)
pleural effusion	1/48 (2.1%)
pneumonitis	2/48 (4.2%)
respiratory failure	1/48 (2.1%)
upper respiratory infection	1/48 (2.1%)
Vascular disorders
hypotension	1/48 (2.1%)
Other (Not Including Serious) Adverse Events
	Pomalidomide, Dexamethasone & MK-3475
	Affected / at Risk (%)	# Events
Total	48/48 (100%)
Blood and lymphatic system disorders
anemia	26/48 (54.2%)
lymphocyte count decreased	14/48 (29.2%)
neutrophil count decreased	30/48 (62.5%)
platelet count decreased	27/48 (56.3%)
white blood cell decreased	28/48 (58.3%)
Cardiac disorders
atrial fibrillation	3/48 (6.3%)
palpitations	6/48 (12.5%)
sinus tachycardia	5/48 (10.4%)
Ear and labyrinth disorders
ear pain	3/48 (6.3%)
Endocrine disorders
hypothyroidism	5/48 (10.4%)
Eye disorders
blurred vision	11/48 (22.9%)
Gastrointestinal disorders
abdominal pain	6/48 (12.5%)
bloating	5/48 (10.4%)
constipation	19/48 (39.6%)
diarrhea	17/48 (35.4%)
gastroesophageal reflux disease	3/48 (6.3%)
nausea	10/48 (20.8%)
stomach pain	3/48 (6.3%)
vomiting	6/48 (12.5%)
General disorders
chest pain- non cardiac	3/48 (6.3%)
chest pain- unspecified	5/48 (10.4%)
chills	5/48 (10.4%)
edema limbs	19/48 (39.6%)
fatigue	23/48 (47.9%)
fever	5/48 (10.4%)
other, common cold	10/48 (20.8%)
pain	3/48 (6.3%)
Infections and infestations
skin infection	4/48 (8.3%)
urinary tract infection	4/48 (8.3%)
Injury, poisoning and procedural complications
bruising	4/48 (8.3%)
fall	10/48 (20.8%)
fracture	4/48 (8.3%)
spinal fracture	3/48 (6.3%)
Investigations
activated partial thromboplastin time prolonged	4/48 (8.3%)
alanine aminotransferase increased	15/48 (31.3%)
alkaline phosphatase increased	7/48 (14.6%)
aspartate aminotransferase increased	15/48 (31.3%)
blood bilirubin increased	4/48 (8.3%)
creatinine increased	19/48 (39.6%)
weight gain	7/48 (14.6%)
weight loss	4/48 (8.3%)
Metabolism and nutrition disorders
hypercalcemia	7/48 (14.6%)
hyperglycemia	30/48 (62.5%)
hyperkalemia	11/48 (22.9%)
hypernatremia	4/48 (8.3%)
hyperuricemia	8/48 (16.7%)
hypoalbuminemia	14/48 (29.2%)
hypocalcemia	16/48 (33.3%)
hypoglycemia	8/48 (16.7%)
hypokalemia	11/48 (22.9%)
hypomagenesemia	15/48 (31.3%)
hyponatremia	18/48 (37.5%)
hypohosphatemia	9/48 (18.8%)
Musculoskeletal and connective tissue disorders
arthralgia	12/48 (25%)
arthritis	4/48 (8.3%)
back pain	20/48 (41.7%)
bone pain	9/48 (18.8%)
chest wall pain	4/48 (8.3%)
flank pain	3/48 (6.3%)
generalized muscle weakness	4/48 (8.3%)
other, muscle cramp	14/48 (29.2%)
pain in extremity	16/48 (33.3%)
Nervous system disorders
dizziness	23/48 (47.9%)
headache	19/48 (39.6%)
other, peripheral neuropathy NOS	5/48 (10.4%)
tremor	9/48 (18.8%)
Psychiatric disorders
anxiety	6/48 (12.5%)
confusion	6/48 (12.5%)
insomnia	13/48 (27.1%)
Respiratory, thoracic and mediastinal disorders
cough	8/48 (16.7%)
dyspnea	26/48 (54.2%)
epitaxis	6/48 (12.5%)
hiccups	3/48 (6.3%)
lung infection	3/48 (6.3%)
nasal congestion	9/48 (18.8%)
pneumonitis	6/48 (12.5%)
sore throat	5/48 (10.4%)
upper respiratory infection	19/48 (39.6%)
Skin and subcutaneous tissue disorders
hyperhidrosis	8/48 (16.7%)
other, rash unspecified	10/48 (20.8%)
pruritis	10/48 (20.8%)
rash maculopapular	11/48 (22.9%)
Vascular disorders
hot flashes	3/48 (6.3%)
hypertension	9/48 (18.8%)
hypotension	8/48 (16.7%)

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.