NCT02407171

Evaluating the Combination of MK-3475 and Sterotactic Body Radiotherapy in Patients With Metastatic Melanoma or NSCLC

Completed Phase 1, PHASE2 Results posted Last updated 31 October 2023

What this trial tests

Phase 1, PHASE2 trial testing MK-3475 in Melanoma in 61 participants. Completed in 19 February 2019.

Timeline

1 April 2015

Primary endpoint
19 February 2019

19 February 2019

Quick facts

Lead sponsor	Yale University
Phase	Phase 1, PHASE2
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	61
Start date	1 April 2015
Primary completion	19 February 2019
Estimated completion	19 February 2019
Sites	1 location across United States

Drugs / interventions tested

• MK-3475 — full drug profile →
• Stereotactic Body Radiation Therapy (SBRT) — full drug profile →

Conditions studied

• Melanoma — all drugs for Melanoma →
• Lung Cancer — all drugs for Lung Cancer →

Sponsor

Yale University

Who can join

18 and older, any sex, with Melanoma or Lung Cancer. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Phase 2, Overall Response Primary · up to 12 months

Phase 2 primary endpoint is the overall response count of patients to post-SBRT MK-3475. Overall response was evaluated using Response Evaluation Criteria In Solid Tumors (RECIST). The following are counts of those that were assessed to have the following responses: Complete response (CR), Partial response (PR), Stable disease (SD), Progressive disease (PD), Not Evaluable.

Group	Value	95% CI
Phase 1: Lung Targets + MK-3475 / Phase 2 NSCLC, no Prior PD-1 Therapy	0
Phase 1: Lung Targets / Phase 2: NSCLC, Previously Treated With Immunotherapy/irPD	0
Phase 1: Non-Lung Target + MK-3475 / Phase 2 Melanoma, no Prior PD-1 Therapy	0
Phase 1: Non-Lung Target / Phase 2: Melanoma, Previously Treated With Immunotherapy/irPD	0
Phase 2: NSCLC or Melanoma, no Prior PD-1 Therapy	0
Phase 2: Melanoma, Previously Treated With Immunotherpay, With irPD	0
Phase 1: Lung Targets + MK-3475 / Phase 2 NSCLC, no Prior PD-1 Therapy	1
Phase 1: Lung Targets / Phase 2: NSCLC, Previously Treated With Immunotherapy/irPD	0
Phase 1: Non-Lung Target + MK-3475 / Phase 2 Melanoma, no Prior PD-1 Therapy	0
Phase 1: Non-Lung Target / Phase 2: Melanoma, Previously Treated With Immunotherapy/irPD	0
Phase 2: NSCLC or Melanoma, no Prior PD-1 Therapy	0
Phase 2: Melanoma, Previously Treated With Immunotherpay, With irPD	0
Phase 1: Lung Targets + MK-3475 / Phase 2 NSCLC, no Prior PD-1 Therapy	4
Phase 1: Lung Targets / Phase 2: NSCLC, Previously Treated With Immunotherapy/irPD	0
Phase 1: Non-Lung Target + MK-3475 / Phase 2 Melanoma, no Prior PD-1 Therapy	2
Phase 1: Non-Lung Target / Phase 2: Melanoma, Previously Treated With Immunotherapy/irPD	2
Phase 2: NSCLC or Melanoma, no Prior PD-1 Therapy	0
Phase 2: Melanoma, Previously Treated With Immunotherpay, With irPD	1
Phase 1: Lung Targets + MK-3475 / Phase 2 NSCLC, no Prior PD-1 Therapy	5
Phase 1: Lung Targets / Phase 2: NSCLC, Previously Treated With Immunotherapy/irPD	3
Phase 1: Non-Lung Target + MK-3475 / Phase 2 Melanoma, no Prior PD-1 Therapy	1
Phase 1: Non-Lung Target / Phase 2: Melanoma, Previously Treated With Immunotherapy/irPD	3
Phase 2: NSCLC or Melanoma, no Prior PD-1 Therapy	0
Phase 2: Melanoma, Previously Treated With Immunotherpay, With irPD	1

Phase 1, Dose-Limiting Toxicity Primary · up to 12 months

Phase 1 primary endpoint will be the presence of a dose limiting toxicity. Maximum tolerated dose will be the highest dose at which there is not a dose limiting toxicity. This could be either 3000 cGy in 5 fractions or 3 fractions. Presented are counts of the maximum tolerated of participants per arm. Results are summarized by Lung or Non-Lung targets overall.

Group	Value	95% CI
Phase 1: SBRT Dose Esc. for Lung Targets + MK-3475	7
Phase 1: SBRT Dose Esc. Non-Lung Target + MK-3475	4
Phase 1: SBRT Dose Esc. for Lung Targets + MK-3475	6
Phase 1: SBRT Dose Esc. Non-Lung Target + MK-3475	7

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to 12 months. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Phase 1: Lung Targets + MK-3475 / Phase 2 NSCLC, no Prior PD-1 Therapy

Serious: 5/10 (50%)

Deaths: 0/10

Phase 1: Lung Targets / Phase 2: NSCLC, Previously Treated With Immunotherapy/irPD

Serious: 0/3 (0%)

Deaths: 0/3

Phase 1: Non-Lung Target + MK-3475 / Phase 2 Melanoma, no Prior PD-1 Therapy

Serious: 1/5 (20%)

Deaths: 1/5

Phase 1: Non-Lung Target / Phase 2: Melanoma, Previously Treated With Immunotherapy/irPD

Serious: 1/6 (17%)

Deaths: 0/6

Phase 2: NSCLC With no Prior PD-1 Therapy

Serious: 13/35 (37%)

Deaths: 3/35

Phase 2: Melanoma, Previously Treated With Immunotherpay, With irPD

Serious: 0/2 (0%)

Deaths: 0/2

Serious adverse events (25 terms)

Reaction	System	Phase 1: Lung Targets + MK…	Phase 1: Lung Targets / Ph…	Phase 1: Non-Lung Target +…	Phase 1: Non-Lung Target /…	Phase 2: NSCLC With no Pri…	Phase 2: Melanoma, Previou…
Pericardial tamponade	Cardiac disorders	—	—	—	—	—	—
Thromboembolic event	Vascular disorders	—	—	—	—	—	—
Infections and infestations - Other	Infections and infestations	—	—	—	—	—	—
Lung infection	Infections and infestations	—	—	—	—	—	—
Device related infection	Infections and infestations	—	—	—	—	—	—
Fracture	Injury, poisoning and procedural complications	—	—	—	—	—	—
Hip fracture	Injury, poisoning and procedural complications	—	—	—	—	—	—
Hyponatremia	Metabolism and nutrition disorders	—	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—	—
Transient ischemic attacks	Nervous system disorders	—	—	—	—	—	—
Confusion	Psychiatric disorders	—	—	—	—	—	—
Atrial flutter	Cardiac disorders	—	—	—	—	—	—
Pericardial effusion	Cardiac disorders	—	—	—	—	—	—
Dyspnea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Pneumonitis	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Respiratory, thoracic and mediastinal disorders - Other	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Bronchopulmonary hemorrhage	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Hypothyroidism	Endocrine disorders	—	—	—	—	—	—
Colitis	Gastrointestinal disorders	—	—	—	—	—	—
Gastric hemorrhage	Gastrointestinal disorders	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—
Non-cardiac chest pain	General disorders	—	—	—	—	—	—

Other adverse events (130 terms — click to expand)

Reaction	System	Phase 1: Lung Targets + MK…	Phase 1: Lung Targets / Ph…	Phase 1: Non-Lung Target +…	Phase 1: Non-Lung Target /…	Phase 2: NSCLC With no Pri…	Phase 2: Melanoma, Previou…
Fatigue	General disorders	—	—	—	—	—	—
Dyspnea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Pain	General disorders	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—
Productive cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
General disorders and administration site conditions - Other	General disorders	—	—	—	—	—	—
Diarrhea	Gastrointestinal disorders	—	—	—	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Rash acneiform	Skin and subcutaneous tissue disorders	—	—	—	—	—	—
Skin and subcutaneous tissue disorders - Other	Skin and subcutaneous tissue disorders	—	—	—	—	—	—
Hypertension	Vascular disorders	—	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—
Edema limbs	General disorders	—	—	—	—	—	—
Anorexia	Metabolism and nutrition disorders	—	—	—	—	—	—
Localized edema	General disorders	—	—	—	—	—	—
Infections and infestations - Other	Infections and infestations	—	—	—	—	—	—
Anxiety	Psychiatric disorders	—	—	—	—	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—	—	—	—	—
Blurred vision	Eye disorders	—	—	—	—	—	—
Watering eyes	Eye disorders	—	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—	—
Non-cardiac chest pain	General disorders	—	—	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Musculoskeletal and connective tissue disorder - Other	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Nervous system disorders - Other	Nervous system disorders	—	—	—	—	—	—
Paresthesia	Nervous system disorders	—	—	—	—	—	—
Pneumonitis	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Sore throat	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Rash maculo-papular	Skin and subcutaneous tissue disorders	—	—	—	—	—	—
Hearing impaired	Ear and labyrinth disorders	—	—	—	—	—	—
Hypothyroidism	Endocrine disorders	—	—	—	—	—	—
Gastrointestinal disorders - Other	Gastrointestinal disorders	—	—	—	—	—	—
Anemia	Blood and lymphatic system disorders	—	—	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—	—	—
Rhinitis infective	Infections and infestations	—	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—	—	—	—

Most-reported serious reactions: Pericardial tamponade, Thromboembolic event, Infections and infestations - Other, Lung infection, Device related infection, Fracture, Hip fracture, Hyponatremia.

Data from ClinicalTrials.gov NCT02407171 adverse events section.

Sponsor's own description

This is a 2-part prospective trial examining the ability of Stereotactic Body Radiation Therapy (SBRT) to induce a response to MK-3475, a humanized antibody to PD-1, in patients who progress on this antibody. Patients with metastatic melanoma will be enrolled after they have progressed on anti-PD-1 therapy. Patients with metastatic NSCLC (previously untreated with anti-PD-1 or anti-PD-L1 therapy) will be enrolled and treated with MK-3475 until they exhibit progression of disease. At this point (when patients have demonstrated progression of disease) a single target lesion will be selected and treated with SBRT, and then MK-3475 will be restarted and continued until there is further progression of disease. The first phase of the study is a radiation dose escalation with a constant dose of MK-3475. The second part of the study includes expansion cohorts of NSCLC and melanoma patients.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Current clinical trials testing the combination of immunotherapy with radiotherapy.
   Kang J, Demaria S, Formenti S. · · 2016 · cited 293× · PMID 27660705 · DOI 10.1186/s40425-016-0156-7
2. SBRT combined with PD-1/PD-L1 inhibitors in NSCLC treatment: a focus on the mechanisms, advances, and future challenges.
   Chen Y, Gao M, Huang Z, Yu J, et al · · 2020 · cited 125× · PMID 32723363 · DOI 10.1186/s13045-020-00940-z
3. Activity and safety of radiotherapy with anti-PD-1 drug therapy in patients with metastatic melanoma.
   Liniker E, Menzies AM, Kong BY, Cooper A, et al · · 2016 · cited 115× · PMID 27757312 · DOI 10.1080/2162402x.2016.1214788
4. Overcoming Resistance to Combination Radiation-Immunotherapy: A Focus on Contributing Pathways Within the Tumor Microenvironment.
   Darragh LB, Oweida AJ, Karam SD. · · 2018 · cited 103× · PMID 30766539 · DOI 10.3389/fimmu.2018.03154
5. Immunotherapy with checkpoint inhibitors in non-small cell lung cancer: insights from long-term survivors.
   Nadal E, Massuti B, Dómine M, García-Campelo R, et al · · 2019 · cited 84× · PMID 30725206 · DOI 10.1007/s00262-019-02310-2
6. Trial Watch: Immunotherapy plus radiation therapy for oncological indications.
   Vacchelli E, Bloy N, Aranda F, Buqué A, et al · · 2016 · cited 61× · PMID 27757313 · DOI 10.1080/2162402x.2016.1214790
7. Current Clinical Progress of PD-1/PD-L1 Immunotherapy and Potential Combination Treatment in Non-Small Cell Lung Cancer.
   Li JX, Huang JM, Jiang ZB, Li RZ, et al · · 2019 · cited 45× · PMID 31838881 · DOI 10.1177/1534735419890020
8. The evolving toxicity profile of SBRT for lung cancer.
   Thompson M, Rosenzweig KE. · · 2019 · cited 45× · PMID 30788234 · DOI 10.21037/tlcr.2018.10.06