Clinical trial NCT01840579: Study of Pembrolizumab (MK-3475) Monotherapy in Advanced Solid Tumors and Pembrolizumab Combination Therapy in Advanced Non-small Cell Lung Cancer/ Extensive-disease Small Cell Lung Cancer (MK-3475-011/KEYNOTE-011)
Official title: A Phase I Study of MK-3475 Alone in Subjects With Advanced Solid Tumors and in Combination With Platinum-Doublet Chemotherapy or Immunotherapy in Subjects With Advanced Non-Small Cell Lung Cancer/Extensive-Disease Small Cell Lung Cancer.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumor
Non-small Cell Lung Cancer
Small Cell Lung Cancer
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2013-04-25
Enrollment: 57
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study using pembrolizumab (MK-3475) will be done in 5 parts. In Part A, successive participant cohorts with advanced solid tumors will receive pembrolizumab to assess the safety and tolerability of monotherapy. In Parts B, C, and D, participants with advanced non-small cell lung cancer (NSCLC) will receive pembrolizumab in combination with either cisplatin/pemetrexed or carboplatin/pemetrexed (Part B); with either carboplatin/paclitaxel or carboplatin/nab-paclitaxel (Part C); or with ipilimumab (Part D) by non-random assignment to assess the safety and tolerability of the combination therapy. In Part E, participants with untreated Extensive-disease (ED) Small Cell Lung Cancer (SCLC) will receive pembrolizumab in combination with either cisplatin/etoposide, carboplatin/etoposide, or cisplatin/etoposide with prophylactic use of granulocyte colony-stimulating factor (lasting G-CSF \[pegfilgrastim\]) by non-random assignment to assess the safety and tolerability of the combination therapy.


Eligibility criteria: Inclusion Criteria:

* In Part A: has a histological or cytological diagnosis of solid tumor, progressive metastatic disease, or progressive locally advanced disease not amenable to local therapy
* In Part B, C, and D: has a histologically- or cytologically-confirmed diagnosis of NSCLC (Stage IIIB/IV) and are naïve to systemic therapy
* In Part C: has a histologically- or cytologically-confirmed diagnosis of squamous cancer
* In Part E: has a histologically- or cytologically-confirmed diagnosis of SCLC (ED stage) and are naïve to systemic therapy
* Has Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
* Has adequate organ function
* Female participants of reproductive potential must not be pregnant (negative urine or serum human chorionic gonadotropin test within 72 hours of study start)
* Female and male participants of reproductive potential must agree to use adequate contraception throughout the study period and for up to 120 days after the last dose of study therapy and for up to 180 days after the last dose of chemotherapeutic agents

Exclusion criteria:

* Has had cancer therapy within 2 weeks (Part E) or 4 weeks (Parts A, B, C, and D) prior to the first dose of study therapy, or not recovered from the adverse events of agents administered more than 4 weeks prior to the first dose of study therapy.

  * Part A: Chemotherapy, radiation therapy, biological therapy or kinase inhibitors
  * Parts B, C, D and E: Radiation therapy
* For Part B: has a histological diagnosis of squamous cancer
* Is currently participating or has participated in a study with an investigational agent or using an investigational device within 30 days of first dose of study therapy
* Is expected to require any other form of antineoplastic therapy while on study
* Is on chronic systemic steroid therapy within two weeks prior to the first dose of trial treatment or on any other form of immunosuppressive medication
* For Part C: Has pre-existing peripheral neuropathy that is ≥ Grade 2 by Common Terminology Criteria for Adverse Events version 4 criteria
* Has interstitial lung disease detected by chest computed tomography (CT), or a history of pneumonitis that required oral or intravenous glucocorticoids to assist with management. Lymphangitic spread of the NSCLC is not exclusionary.

Primary outcomes:
measure: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)
timeFrame: Cycle 1 (first dose and up to 4 weeks in Part A, 3 weeks in Parts B, C, E, and 6 weeks in Part D)
measure: Number of Participants Who Experienced at Least One Adverse Event (AE)
timeFrame: Up to approximately 51.3 months
measure: Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
timeFrame: Up to approximately 37.9 months
Secondary outcomes:
measure: Maximum Serum Concentration (Cmax) of Pembrolizumab for Cycle 1: Parts A, B, C, D, and E
timeFrame: At designated timepoints in Cycle 1 for Parts A, B, C, D, and E (up to approximately 22 days)
measure: Maximum Serum Concentration (Cmax) of Pembrolizumab for Cycle 2: Part A
timeFrame: Cycle 2 Day 1 pre- and post-dose
measure: Maximum Serum Concentration (Cmax) of Pembrolizumab for Cycle 4: Parts A and D
timeFrame: Cycle 4 Day 1 pre- and post-dose (Part A) and Day 22 pre-dose (Day 1 of the following cycle prior to pembrolizumab infusion) and post-dose (Part D)
measure: Maximum Serum Concentration (Cmax) of Pembrolizumab for Cycle 6: Part A
timeFrame: Cycle 6 Day 1 pre- and post-dose
measure: Maximum Serum Concentration (Cmax) of Pembrolizumab for Cycle 8: Parts A, B, C, and E
timeFrame: Cycle 8 Day 1 pre- and post-dose
measure: Maximum Serum Concentration (Cmax) of Pembrolizumab for Cycle 10: Part A
timeFrame: Cycle 10 Day 1 pre- and post-dose
measure: Maximum Serum Concentration (Cmax) of Pembrolizumab for Cycle 12: Part A
timeFrame: Cycle 12 Day 1 pre- and post-dose
measure: Maximum Serum Concentration (Cmax) of Pembrolizumab for Cycle 14: Part A
timeFrame: Cycle 14 Day 1 pre- and post-dose
measure: Maximum Serum Concentration (Cmax) of Pembrolizumab for Cycle 16: Part A
timeFrame: Cycle 16 Day 1 pre- and post-dose
measure: Maximum Serum Concentration (Cmax) of Pembrolizumab for Cycle 18: Part A
timeFrame: Cycle 18 Day 1 pre- and post-dose
measure: Time to Maximum Serum Concentration (Tmax) of Pembrolizumab for Cycle 1: Parts A, B, C, D, and E
timeFrame: At designated timepoints in Cycle 1 for Parts A, B, C, D, and E (up to approximately 22 days)
measure: Time to Maximum Serum Concentration (Tmax) of Pembrolizumab for Cycle 4: Part D
timeFrame: Cycle 4 Day 22 pre-dose (Day 1 of the following cycle prior to pembrolizumab infusion) and post-dose
measure: Time to Maximum Serum Concentration (Tmax) of Pembrolizumab for Cycle 8: Parts B, C, and E
timeFrame: Cycle 8 Day 1 pre- and post-dose
measure: Trough Concentration (Ctrough) of Pembrolizumab for Cycle 1: Parts A, B, C, D, and E
timeFrame: Cycle 2 Day 1 pre-dose
measure: Trough Concentration (Ctrough) of Pembrolizumab for Cycle 2: Part D
timeFrame: Cycle 2 Day 22 pre-dose
measure: Trough Concentration (Ctrough) of Pembrolizumab for Cycle 3: Part D
timeFrame: Cycle 3 Day 22 pre-dose
measure: Trough Concentration (Ctrough) of Pembrolizumab for Cycle 3: Parts A, B, C, and E
timeFrame: Cycle 4 Day 1 at Pre-dose
measure: Trough Concentration (Ctrough) of Pembrolizumab for Cycle 4: Part D
timeFrame: Cycle 4 Day 22 pre-dose
measure: Trough Concentration (Ctrough) of Pembrolizumab for Cycle 5: Parts A, B, C, and E
timeFrame: Cycle 6 Day 1 pre-dose
measure: Trough Concentration (Ctrough) of Pembrolizumab for Cycle 6: Part D
timeFrame: Cycle 6 Day 22 pre-dose
measure: Trough Concentration (Ctrough) of Pembrolizumab for Cycle 7: Parts A, B, C, and E
timeFrame: Cycle 8 Day 1 pre-dose
measure: Trough Concentration (Ctrough) of Pembrolizumab for Cycle 8: Part D
timeFrame: Cycle 8 Day 22 pre-dose
measure: Trough Concentration (Ctrough) of Pembrolizumab for Cycle 9: Part A
timeFrame: Cycle 10 Day 1 pre-dose
measure: Trough Concentration (Ctrough) of Pembrolizumab for Cycle 10: Part D
timeFrame: Cycle 10 Day 22 pre-dose
measure: Trough Concentration (Ctrough) of Pembrolizumab for Cycle 11: Parts A, B, C, and E
timeFrame: Cycle 12 Day 1 Pre-dose
measure: Trough Concentration (Ctrough) of Pembrolizumab for Cycle 12: Part D
timeFrame: Cycle 12 Day 22 pre-dose
measure: Trough Concentration (Ctrough) of Pembrolizumab for Cycle 13: Part A
timeFrame: Cycle 14 Day 1 pre-dose
measure: Trough Concentration (Ctrough) of Pembrolizumab for Cycle 14: Part D
timeFrame: Cycle 14 Day 22 pre-dose
measure: Trough Concentration (Ctrough) of Pembrolizumab for Cycle 15: Parts A, B, C, and E
timeFrame: Cycle 16 Day 1 pre-dose
measure: Trough Concentration (Ctrough) of Pembrolizumab for Cycle 16: Part D
timeFrame: Cycle 16 Day 22 pre-dose
measure: Trough Concentration (Ctrough) of Pembrolizumab for Cycle 17: Part A
timeFrame: Cycle 18 Day 1 pre-dose
measure: Trough Concentration (Ctrough) of Pembrolizumab for Cycle 19: Parts B, C, and E
timeFrame: Cycle 20 Day 1 Pre-dose
measure: Trough Concentration (Ctrough) of Pembrolizumab for Cycle 23: Parts B, C, and E
timeFrame: Cycle 24 Day 1 Pre-dose
measure: Trough Concentration (Ctrough) of Pembrolizumab for Cycle 27: Parts B, C, and E
timeFrame: Cycle 28 Day 1 Pre-dose
measure: Area Under the Concentration Time Curve From 0-28 Days (AUC 0-28) for Part A Cycle 1
timeFrame: At designated timepoints in Cycle 1 for Part A (Up to approximately 28 days)
measure: Area Under the Concentration Time Curve From 0-Infinity (AUC 0-inf) for Part A Cycle 1
timeFrame: At designated timepoints in Cycle 1 for Part A (Up to approximately 28 days)
measure: Terminal Half-Life (t1/2) of Pembrolizumab Over Time for Part A Cycle 1
timeFrame: At designated timepoints in Cycle 1 for Part A (Up to approximately 28 days)
measure: Volume of Distribution (Vz) of Pembrolizumab Over Time for Part A Cycle 1
timeFrame: At designated timepoints in Cycle 1 for Part A (Up to approximately 28 days)
measure: Clearance (CL) of Pembrolizumab Over Time for Part A Cycle 1
timeFrame: At designated timepoints in Cycle 1 for Part A (Up to approximately 28 days)
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Shimizu T, Seto T, Hirai F, Takenoyama M, Nosaki K, Tsurutani J, Kaneda H, Iwasa T, Kawakami H, Noguchi K, Shimamoto T, Nakagawa K. Phase 1 study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced solid tumors. Invest New Drugs. 2016 Jun;34(3):347-54. doi: 10.1007/s10637-016-0347-6. Epub 2016 Mar 22.
citation: Kurata T, Nakagawa K, Satouchi M, Seto T, Sawada T, Han S, Homma M, Noguchi K, Nogami N. Phase 1 study of pembrolizumab plus chemotherapy as first-line treatment in Japanese patients with advanced NSCLC. Cancer Treat Res Commun. 2021;29:100458. doi: 10.1016/j.ctarc.2021.100458. Epub 2021 Sep 15.