MK-3475 in Melanoma and NSCLC Patients With Brain Metastases

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ClinicalTrials.gov Identifier: NCT02085070

Recruitment Status : Completed

First Posted : March 12, 2014

Results First Posted : March 24, 2021

Last Update Posted : March 24, 2021

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Sponsor:

Information provided by (Responsible Party):

Harriet Kluger, Yale University

Study Type	Interventional
Study Design	Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Conditions	Melanoma Non-Small Cell Lung Cancer Brain Metastases
Intervention	Drug: MK-3475
Enrollment	65

Participant Flow

Recruitment Details	29 NSCLC patients were ineligible based on PD-L1.
Pre-assignment Details	Patients were assigned to a cohort based on tumor type.


Arm/Group Title	Melanoma Patients	Non-small Cell Lung Cancer Patients
Arm/Group Description	After establishing eligibility crit...	NSCLC patients are not required to ...
Arm/Group Description	After establishing eligibility criteria, for patients with melanoma the investigator will determine at least one lesion that requires local therapy (surgical resection or LITT) based on size, location, and/or risk of hemorrhage; this will be considered the "surgical lesion". All other eligible brain lesions will be considered "clinically evaluable lesions" and will be followed by modified RECIST (mRECIST) criteria to determine best response. MK-3475: IV MK-3475	NSCLC patients are not required to have a "surgical lesion" but must have at least one "clinically evaluable lesion" in the central nervous system. Patients on NSCLC are required to have formalin-fixed, paraffin-embedded tumor tissue available for biomarker analysis. MK-3475: IV MK-3475
Period Title: Overall Study
Started	23	42
Completed	23	42
Not Completed	0	0

Baseline Characteristics

Arm/Group Title		Melanoma Patients	Non-small Cell Lung Cancer Patients	Total
Arm/Group Description		After establishing eligibility crit...	NSCLC patients are not required to ...	Total of all reporting groups
Arm/Group Description		After establishing eligibility criteria, for patients with melanoma the investigator will determine at least one lesion that requires local therapy (surgical resection or LITT) based on size, location, and/or risk of hemorrhage; this will be considered the "surgical lesion". All other eligible brain lesions will be considered "clinically evaluable lesions" and will be followed by modified RECIST (mRECIST) criteria to determine best response. MK-3475: IV MK-3475	NSCLC patients are not required to have a "surgical lesion" but must have at least one "clinically evaluable lesion" in the central nervous system. Patients on NSCLC are required to have formalin-fixed, paraffin-embedded tumor tissue available for biomarker analysis. MK-3475: IV MK-3475	Total of all reporting groups
Overall Number of Baseline Participants		23	42	65
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Categorical Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	23 participants	42 participants	65 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	10 43.5%	27 64.3%	37 56.9%
	>=65 years	13 56.5%	15 35.7%	28 43.1%
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	23 participants	42 participants	65 participants
	Female	8 34.8%	28 66.7%	36 55.4%
	Male	15 65.2%	14 33.3%	29 44.6%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	23 participants	42 participants	65 participants
	Hispanic or Latino	0 0.0%	4 9.5%	4 6.2%
	Not Hispanic or Latino	23 100.0%	36 85.7%	59 90.8%
	Unknown or Not Reported	0 0.0%	2 4.8%	2 3.1%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	23 participants	42 participants	65 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	1 2.4%	1 1.5%
	Native Hawaiian or Other Pacific Islander	0 0.0%	1 2.4%	1 1.5%
	Black or African American	0 0.0%	1 2.4%	1 1.5%
	White	23 100.0%	35 83.3%	58 89.2%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	4 9.5%	4 6.2%
Region of Enrollment Measure Type: Number Unit of measure: Participants
United States	Number Analyzed	23 participants	42 participants	65 participants
United States		23	42	65

Outcome Measures

1.Primary Outcome


Title	Overall Response in the Brain by mRECIST
Description	RECIST criteria v1.1 was modified to account for differences in measur...
Description	RECIST criteria v1.1 was modified to account for differences in measuring the response of clinically evaluable brain lesions as opposed to systemic lesions (modified RECIST, or mRECIST). Size was considered the tumor's largest diameter. Measurements from multiple lesions were summed to calculate the sum of the diameters (SD). The SD calculated on a baseline scan performed within 28 days of study drug initiation was used as a reference to determine the objective response of the clinically evaluable lesions. mRECIST differ from RECIST v1.0 in allowing lesions measuring 5mm or less for response evaluation, provided that the MRI slice thickness was no more than 2.5mm. Seeing that the primary trial endpoint was brain metastasis response, up to 5 lesions were used for evaluation. Complete response (CR) constitutes complete disappearance of all target lesions, partial response (PR) constitutes >= 30% decrease in the sum of the sum of the largest diameter of target
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

modified RECIST 1.1 was used to determine response


Arm/Group Title	Melanoma Patients	Non-small Cell Lung Cancer Patients
Arm/Group Description:	After establishing eligibility crit...	NSCLC patients are not required to ...
Arm/Group Description:	After establishing eligibility criteria, for patients with melanoma the investigator will determine at least one lesion that requires local therapy (surgical resection or LITT) based on size, location, and/or risk of hemorrhage; this will be considered the "surgical lesion". All other eligible brain lesions will be considered "clinically evaluable lesions" and will be followed by modified RECIST (mRECIST) criteria to determine best response. MK-3475: IV MK-3475	NSCLC patients are not required to have a "surgical lesion" but must have at least one "clinically evaluable lesion" in the central nervous system. Patients on NSCLC are required to have formalin-fixed, paraffin-embedded tumor tissue available for biomarker analysis. MK-3475: IV MK-3475
Overall Number of Participants Analyzed	23	42
Measure Type: Number Unit of Measure: participants
progression/stable	17	31
better response	6	11

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Non-small Cell Lung Cancer Patients
	Comments	Each group was assessed individually. The primary goal of this study is to determine the efficacy of MK-3475 in patients with untreated brain metastases from NSCLC. The primary endpoint is the brain metastasis response rate (BMRR). A drug with minimal activity would be expected to have a BMRR of 10%.
	Type of Statistical Test	Superiority
	Comments	A response of > 10% of patients was defined as superior.

Method of Estimation	Estimation Parameter	% response
	Estimated Value	29.7
	Confidence Interval	(2-Sided) 95% 15.9 to 47.0
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Melanoma Patients
	Comments	Each group was assessed individually. The primary goal of this study is to determine the efficacy of MK-3475 in patients with untreated brain metastases from melanoma. The primary endpoint is the brain metastasis response rate (BMRR). A drug with minimal activity would be expected to have a BMRR of 10%.
	Type of Statistical Test	Superiority
	Comments	A response of > 10% of patients was defined as superior.

Method of Estimation	Estimation Parameter	% of patients
	Estimated Value	26.0
	Confidence Interval	(2-Sided) 95% 10.0 to 48.0
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	2 Years
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	Melanoma Patients		Non-small Cell Lung Cancer Patients
Arm/Group Description	After establishing eligibility crit...		NSCLC patients are not required to ...
Arm/Group Description	After establishing eligibility criteria, for patients with melanoma the investigator will determine at least one lesion that requires local therapy (surgical resection or LITT) based on size, location, and/or risk of hemorrhage; this will be considered the "surgical lesion". All other eligible brain lesions will be considered "clinically evaluable lesions" and will be followed by modified RECIST (mRECIST) criteria to determine best response. MK-3475: IV MK-3475		NSCLC patients are not required to have a "surgical lesion" but must have at least one "clinically evaluable lesion" in the central nervous system. Patients on NSCLC are required to have formalin-fixed, paraffin-embedded tumor tissue available for biomarker analysis. MK-3475: IV MK-3475
All-Cause Mortality
	Melanoma Patients		Non-small Cell Lung Cancer Patients
	Affected / at Risk (%)		Affected / at Risk (%)
Total	16/23 (69.57%)		35/42 (83.33%)
Serious Adverse Events Serious Adverse Events
	Melanoma Patients		Non-small Cell Lung Cancer Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/23 (21.74%)		5/42 (11.90%)
Endocrine disorders
Adrenal Insufficienvy ^† 1	0/23 (0.00%)	0	1/42 (2.38%)	1
Gastrointestinal disorders
Colitis ^† 1	0/23 (0.00%)	0	1/42 (2.38%)	1
General disorders
Fever ^† 1	1/23 (4.35%)	1	0/42 (0.00%)	0
Metabolism and nutrition disorders
Hypokalemia ^† 1	0/23 (0.00%)	0	1/42 (2.38%)	1
Nervous system disorders
Seizure ^† 1	1/23 (4.35%)	1	0/42 (0.00%)	0
Psychiatric disorders
Confusion ^† 1	2/23 (8.70%)	2	0/42 (0.00%)	0
Renal and urinary disorders
Acute Kidney Injury ^† 1	0/23 (0.00%)	0	1/42 (2.38%)	1
Respiratory, thoracic and mediastinal disorders
Pneumonitis ^† 1	0/23 (0.00%)	0	2/42 (4.76%)	2
Skin and subcutaneous tissue disorders
Rash ^† 1	1/23 (4.35%)	1	0/42 (0.00%)	0
1 Term from vocabulary, CTCAE (4.0) † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Melanoma Patients		Non-small Cell Lung Cancer Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/23 (56.52%)		35/42 (83.33%)
Endocrine disorders
Hypothyroidism ^† 1	1/23 (4.35%)	1	6/42 (14.29%)	8
Eye disorders
Floaters ^† 1	0/23 (0.00%)	0	4/42 (9.52%)	5
Gastrointestinal disorders
Abdominal pain ^† 1	2/23 (8.70%)	2	6/42 (14.29%)	6
Colitis ^† 1	2/23 (8.70%)	2	0/42 (0.00%)	0
Constipation ^† 1	2/23 (8.70%)	2	21/42 (50.00%)	30
Diarrhea ^† 1	3/23 (13.04%)	3	14/42 (33.33%)	26
Nausea ^† 1	7/23 (30.43%)	7	12/42 (28.57%)	17
Vomiting ^† 1	2/23 (8.70%)	2	4/42 (9.52%)	6
Dyspepsia ^† 1	0/23 (0.00%)	0	3/42 (7.14%)	3
Gastroesophageal reflux disease ^† 1	0/23 (0.00%)	0	3/42 (7.14%)	4
General disorders
Chills ^† 1	2/23 (8.70%)	2	1/42 (2.38%)	1
Fatigue ^† 1	13/23 (56.52%)	13	35/42 (83.33%)	65
Edema limbs ^† 1	0/23 (0.00%)	0	10/42 (23.81%)	14
Fever ^† 1	1/23 (4.35%)	1	3/42 (7.14%)	5
Non-cardiac chest pain ^† 1	0/23 (0.00%)	0	5/42 (11.90%)	5
Investigations
Alanine aminotransferase increased ^† 1	0/23 (0.00%)	0	3/42 (7.14%)	5
Aspartate aminotransferase increased ^† 1	0/23 (0.00%)	0	3/42 (7.14%)	4
Creatinine increased ^† 1	0/23 (0.00%)	0	3/42 (7.14%)	4
Metabolism and nutrition disorders
Anorexia ^† 1	0/23 (0.00%)	0	17/42 (40.48%)	25
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	2/23 (8.70%)	2	3/42 (7.14%)	3
Back pain ^† 1	2/23 (8.70%)	2	18/42 (42.86%)	26
Pain ^† 1	3/23 (13.04%)	4	4/42 (9.52%)	10
Bone pain ^† 1	0/23 (0.00%)	0	3/42 (7.14%)	5
Chest wall pain ^† 1	0/23 (0.00%)	0	3/42 (7.14%)	4
Muscle weakness lower limb ^† 1	1/23 (4.35%)	1	4/42 (9.52%)	6
Neck pain ^† 1	0/23 (0.00%)	0	3/42 (7.14%)	3
Pain in extremity ^† 1	1/23 (4.35%)	1	13/42 (30.95%)	25
Nervous system disorders
Ataxia ^† 1	3/23 (13.04%)	3	0/42 (0.00%)	0
Cognitive disturbance ^† 1	2/23 (8.70%)	2	2/42 (4.76%)	2
Confusion ^† 1	2/23 (8.70%)	2	0/42 (0.00%)	0
Dizziness ^† 1	2/23 (8.70%)	2	10/42 (23.81%)	13
Dysphasia ^† 1	2/23 (8.70%)	2	0/42 (0.00%)	0
Gait disturbance ^† 1	2/23 (8.70%)	2	0/42 (0.00%)	0
Headache ^† 1	3/23 (13.04%)	3	15/42 (35.71%)	30
Seizure ^† 1	1/23 (4.35%)	1	3/42 (7.14%)	5
Psychiatric disorders
Anxiety ^† 1	1/23 (4.35%)	1	9/42 (21.43%)	11
Depression ^† 1	0/23 (0.00%)	0	3/42 (7.14%)	3
Insomnia ^† 1	0/23 (0.00%)	0	7/42 (16.67%)	8
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	3/23 (13.04%)	3	26/42 (61.90%)	42
Nasal congestion ^† 1	2/23 (8.70%)	2	2/42 (4.76%)	3
Allergic rhinitis ^† 1	1/23 (4.35%)	1	5/42 (11.90%)	7
Dyspnea ^† 1	0/23 (0.00%)	0	21/42 (50.00%)	28
Skin and subcutaneous tissue disorders
Pruritus ^† 1	4/23 (17.39%)	4	5/42 (11.90%)	9
Rash maculo-papular ^† 1	3/23 (13.04%)	3	10/42 (23.81%)	11
Vascular disorders
Hypertension ^† 1	0/23 (0.00%)	0	7/42 (16.67%)	8
Thromboembolic event ^† 1	0/23 (0.00%)	0	6/42 (14.29%)	7
1 Term from vocabulary, CTCAE (4.0) † 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

Layout table for Results Point of Contact information

Name/Title:	Director, Clinical Trials Office
Organization:	Yale Cancer Center
Phone:	12037372572
EMail:	Joyce.Tull@yale.edu

Publications:

Goldberg SB, Schalper KA, Gettinger SN, Mahajan A, Herbst RS, Chiang AC, Lilenbaum R, Wilson FH, Omay SB, Yu JB, Jilaveanu L, Tran T, Pavlik K, Rowen E, Gerrish H, Komlo A, Gupta R, Wyatt H, Ribeiro M, Kluger Y, Zhou G, Wei W, Chiang VL, Kluger HM. Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial. Lancet Oncol. 2020 May;21(5):655-663. doi: 10.1016/S1470-2045(20)30111-X. Epub 2020 Apr 3.

Kluger HM, Chiang V, Mahajan A, Zito CR, Sznol M, Tran T, Weiss SA, Cohen JV, Yu J, Hegde U, Perrotti E, Anderson G, Ralabate A, Kluger Y, Wei W, Goldberg SB, Jilaveanu LB. Long-Term Survival of Patients With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a Phase II Trial. J Clin Oncol. 2019 Jan 1;37(1):52-60. doi: 10.1200/JCO.18.00204. Epub 2018 Nov 8.

Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, Tsiouris AJ, Cohen J, Vortmeyer A, Jilaveanu L, Yu J, Hegde U, Speaker S, Madura M, Ralabate A, Rivera A, Rowen E, Gerrish H, Yao X, Chiang V, Kluger HM. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol. 2016 Jul;17(7):976-983. doi: 10.1016/S1470-2045(16)30053-5. Epub 2016 Jun 3.

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

Qian JM, Yu JB, Mahajan A, Goldberg SB, Kluger HM, Chiang VLS. Frequent Use of Local Therapy Underscores Need for Multidisciplinary Care in the Management of Patients With Melanoma Brain Metastases Treated With PD-1 Inhibitors. Int J Radiat Oncol Biol Phys. 2019 Dec 1;105(5):1113-1118. doi: 10.1016/j.ijrobp.2019.08.053. Epub 2019 Aug 31.

Qian JM, Mahajan A, Yu JB, Tsiouris AJ, Goldberg SB, Kluger HM, Chiang VLS. Comparing available criteria for measuring brain metastasis response to immunotherapy. J Neurooncol. 2017 May;132(3):479-485. doi: 10.1007/s11060-017-2398-8. Epub 2017 Mar 8.

Layout table for additonal information

Responsible Party:	Harriet Kluger, Yale University
ClinicalTrials.gov Identifier:	NCT02085070
Other Study ID Numbers:	1401013290 IND 121564 ( Other Identifier: FDA )
First Submitted:	March 10, 2014
First Posted:	March 12, 2014
Results First Submitted:	February 23, 2021
Results First Posted:	March 24, 2021
Last Update Posted:	March 24, 2021

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