Pembrolizumab Effects on NK Cell Exhaustion in Melanoma (Merck NK-IIT)

• Sponsor: Nina Bhardwaj (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03241927
• Collaborator: (none)
• Enrollment: 1
• Location: 1
• Arms: 2
• Actual Duration (Months): 5.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Melanoma is an immune-modulated malignancy and immune checkpoint modulators which inhibit PD-1 function (pembrolizumab, nivolumab) have demonstrated clinical efficacy as treatment for patients with stage IV melanoma. Pembrolizumab across a range of doses in phase I investigation has demonstrated clinical efficacy with RR approximately 27%. By better understanding how NK cell function and exhaustion interplays with PD1 function and activity, potentially more efficacious combination therapies can be developed. The pharmacodynamic studies to be performed as part of this trial will provide such information.

Condition or Disease	Intervention/Treatment	Phase
Melanoma	Biological: Pembrolizumab	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study Assessing the Effect of Pembrolizumab Induced Changes to the NK Cell Exhaustion Phenotype on the Efficacy of PD-1 Targeted Treatment in Patients With Unresectable Stage III or Stage IV Melanoma
• Actual Study Start Date: Dec 20, 2017
• Actual Primary Completion Date: Jun 6, 2018
• Actual Study Completion Date: Jun 6, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pembrolizumab 200 mg IV infusion every 3 weeks	Biological: Pembrolizumab; Day 1 of each 3 week cycle
No Intervention: Healthy Donors

Outcome Measures

Primary Outcome Measures

1. Percent of LAMP-1 Positive Cells [up to 3 years]

   NK cell exhaustion will be assess by flow cytometry and expressed as % of LAMP-1 positive cells.

2. Percent of Positive Cell for IFN Gamma [up to 3 years]

   IFN gamma will be assess by flow cytometry and then expressed as % of positive cell for IFN gamma.

3. Percent of Proliferating Cells [up to 3 years]

   NK proliferation will be assess by flow cytometry and then expressed as percentage of proliferating cells.

Secondary Outcome Measures

1. MICA Plasma Level [up to 104 levels]

   MICA plasma biomarker level associated with reversal of NK cell exhaustion will be assessed by ELISA.

2. HMGB-1 Plasma Level [up to 104 weeks]

   HMGB-1 plasma biomarker level associated with reversal of NK cell exhaustion will be assessed by ELISA.

3. % of Positive NK Cells for CEACAM-1 [up to 104 weeks]

   CEACAM-1 expression will be assessed by flow cytometry and express as % of positive NK cells for CEACAM-1

4. Incidence of Overall Survival [1 year]

   One year survival following pembrolizumab treatment in patients with Unresectable stage III or IV melanoma using Immune-Related Response Criteria.

5. Progression Free Survival (PFS) Rate [6 months]

   Progression free survival in pembrolizumab treated patients with unresectable stage III or IV melanoma using Immune-Related Response Criteria.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

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

• Have Unresectable stage III or stage IV melanoma

• Be ≥ 18 years of age on day of signing informed consent.

• Have measurable disease based on RECIST 1.1 and be able to be followed over time by Immune related response criteria (irRC) for treatment decisions.

• Have a performance status of 0, 1, or 2 on the ECOG Performance Scale.

• Demonstrate adequate organ function as defined in Table 1, all screening labs should be performed within 10 days of treatment initiation.

• Female subjects 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 (Reference Section 5.6.2). 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.

Exclusion Criteria:

• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to the first dose of treatment.

• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of systemic immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Topical, inhaled, ocular, and intra-articular steroids are not exclusionary.

• Has a known history of active TB (Bacillus Tuberculosis).

• Hypersensitivity to pembrolizumab or any of its excipients.

• Has had a prior anti-cancer monoclonal antibody (mAb) treatment 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 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. - Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.

• Note: If subject received major surgery, the subject must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.

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

• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided the subjects 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. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability.

• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.

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

• If 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, or anti-PD-L2 agent.

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

• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).

• Has received a live vaccine within 30 days of planned start of study therapy.

• Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines and are not allowed.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029

Sponsors and Collaborators

• Nina Bhardwaj

Investigators

• Principal Investigator: Nina Bhardwaj, MD, PhD, Icahn School of Medicine at Mount Sinai

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 23, 2017

More Information

Publications

None provided.

• Responsible Party: Nina Bhardwaj, Professor, Icahn School of Medicine at Mount Sinai
• ClinicalTrials.gov Identifier: NCT03241927
• Other Study ID Numbers: GCO 16-2526
• First Posted: Aug 8, 2017
• Last Update Posted: Nov 23, 2020
• Last Verified: Oct 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Nina Bhardwaj, Professor, Icahn School of Medicine at Mount Sinai: Pembrolizumab; NK Cell Exhaustion; PD-1; Unresectable; Stage III; Stage IV
• Additional relevant MeSH terms: Melanoma; Pembrolizumab

Study Results

Participant Flow

Recruitment Details	4 Participants consented, 1 with unstable CNS and not eligible, 2 withdrew consent. and 1 enrolled.

Arm/Group Title	Pembrolizumab	Healthy Donors
Arm/Group Description	200 mg IV infusion every 3 weeks Pembrolizumab: Day 1 of each 3 week cycle	Healthy participants
Period Title: Overall Study
STARTED	1	0
COMPLETED	0	0
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Pembrolizumab
Arm/Group Description	200 mg IV infusion every 3 weeks Pembrolizumab: Day 1 of each 3 week cycle
Overall Participants	1
Age, Customized (Count of Participants)
60-69 years	1 100%
70-79 years	0 0%
80-89 years	0 0%
Sex: Female, Male (Count of Participants)
Female	1 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 100%
Not Hispanic or Latino	0 0%
Unknown or Not Reported	0 0%
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	0 0%
White	1 100%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Percent of LAMP-1 Positive Cells
Description	NK cell exhaustion will be assess by flow cytometry and expressed as % of LAMP-1 positive cells.
Time Frame	up to 3 years

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Pembrolizumab	Healthy Donors
Arm/Group Description	200 mg IV infusion every 3 weeks Pembrolizumab: Day 1 of each 3 week cycle	Healthy participants
Measure Participants	0	0

2. Primary Outcome

Title	Percent of Positive Cell for IFN Gamma
Description	IFN gamma will be assess by flow cytometry and then expressed as % of positive cell for IFN gamma.
Time Frame	up to 3 years

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Pembrolizumab	Healthy Donors
Arm/Group Description	200 mg IV infusion every 3 weeks Pembrolizumab: Day 1 of each 3 week cycle	Healthy participants
Measure Participants	0	0

3. Primary Outcome

Title	Percent of Proliferating Cells
Description	NK proliferation will be assess by flow cytometry and then expressed as percentage of proliferating cells.
Time Frame	up to 3 years

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Pembrolizumab	Healthy Donors
Arm/Group Description	200 mg IV infusion every 3 weeks Pembrolizumab: Day 1 of each 3 week cycle	Healthy participants
Measure Participants	0	0

4. Secondary Outcome

Title	MICA Plasma Level
Description	MICA plasma biomarker level associated with reversal of NK cell exhaustion will be assessed by ELISA.
Time Frame	up to 104 levels

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Pembrolizumab	Healthy Donors
Arm/Group Description	200 mg IV infusion every 3 weeks Pembrolizumab: Day 1 of each 3 week cycle	Healthy participants
Measure Participants	0	0

5. Secondary Outcome

Title	HMGB-1 Plasma Level
Description	HMGB-1 plasma biomarker level associated with reversal of NK cell exhaustion will be assessed by ELISA.
Time Frame	up to 104 weeks

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Pembrolizumab	Healthy Donors
Arm/Group Description	200 mg IV infusion every 3 weeks Pembrolizumab: Day 1 of each 3 week cycle	Healthy participants
Measure Participants	0	0

6. Secondary Outcome

Title	% of Positive NK Cells for CEACAM-1
Description	CEACAM-1 expression will be assessed by flow cytometry and express as % of positive NK cells for CEACAM-1
Time Frame	up to 104 weeks

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Pembrolizumab	Healthy Donors
Arm/Group Description	200 mg IV infusion every 3 weeks Pembrolizumab: Day 1 of each 3 week cycle	Healthy participants
Measure Participants	0	0

7. Secondary Outcome

Title	Incidence of Overall Survival
Description	One year survival following pembrolizumab treatment in patients with Unresectable stage III or IV melanoma using Immune-Related Response Criteria.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Pembrolizumab	Healthy Donors
Arm/Group Description	200 mg IV infusion every 3 weeks Pembrolizumab: Day 1 of each 3 week cycle	Healthy participants
Measure Participants	0	0

8. Secondary Outcome

Title	Progression Free Survival (PFS) Rate
Description	Progression free survival in pembrolizumab treated patients with unresectable stage III or IV melanoma using Immune-Related Response Criteria.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

only one subject in study

Arm/Group Title	Pembrolizumab	Healthy Donors
Arm/Group Description	200 mg IV infusion every 3 weeks Pembrolizumab: Day 1 of each 3 week cycle	Healthy participants
Measure Participants	1	0
Number [weeks]	18

Adverse Events

Time Frame	18 weeks
Adverse Event Reporting Description	there was only one person in this study. No participants in Healthy Control arm.
Arm/Group Title	Pembrolizumab		Healthy Control
Arm/Group Description	200 mg IV infusion every 3 weeks Pembrolizumab: Day 1 of each 3 week cycle		Healthy Participants
All Cause Mortality
	Pembrolizumab		Healthy Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/0 (NaN)
Serious Adverse Events
	Pembrolizumab		Healthy Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Pembrolizumab		Healthy Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1 (100%)		0/0 (NaN)
Blood and lymphatic system disorders
Anemia	1/1 (100%)	3	0/0 (NaN)	3
General disorders
Bilateral Leg Edema	1/1 (100%)	1	0/0 (NaN)	1
Investigations
Creatinine Increased	1/1 (100%)	1	0/0 (NaN)	1
Metabolism and nutrition disorders
Hyperuricemia	1/1 (100%)	2	0/0 (NaN)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor Pain	1/1 (100%)	1	0/0 (NaN)	1
Respiratory, thoracic and mediastinal disorders
Pneumonitis	1/1 (100%)	1	0/0 (NaN)	1
Skin and subcutaneous tissue disorders
Hair thinning	1/1 (100%)	1	0/0 (NaN)	1

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.