Phase II Trial of Continuation Therapy in Advanced NSCLC

• ClinicalTrials.gov Identifier: NCT03083808
• Recruitment Status: Active, not recruiting
• First Posted: March 20, 2017
• Results First Posted: June 28, 2022
• Last Update Posted: June 28, 2022
• Sponsor: Greg Durm, MD
• Collaborators: Merck Sharp & Dohme LLC; Big Ten Cancer Research Consortium
• Information provided by (Responsible Party): Greg Durm, MD, Big Ten Cancer Research Consortium

Study Description

Brief Summary:

This is a single-arm phase II study of continuation immunotherapy with pembrolizumab following initial benefit (CR, PR, or SD ≥ 3 months) with a PD-1 or PD-L1 inhibitor.

Condition or disease	Intervention/treatment	Phase
Non-Small-Cell Lung Cancer	Drug: Pembrolizumab	Phase 2

Detailed Description:

OUTLINE: This is a multi-center study.

Patients who have been treated with a PD-1 or PD-L1 inhibitor and experienced a PFS of ≥3 months will be enrolled within 6 weeks of last dose of PD-1 or PD-L1 inhibitor. On Day 1 of each 3-week cycle, subjects will first receive pembrolizumab at a dose of 200mg IV every three weeks in combination with chemotherapy. Partner chemotherapy will be either gemcitabine 1000mg/m2 IV D1 and D8 every three weeks, docetaxel 75mg/m2 IV D1 every three weeks, or pemetrexed 500mg/m2 IV D1 every 3 weeks (pemetrexed for non-squamous histologies only). Subjects will continue to receive this combination until progression or intolerable toxicity.

Administration Sequence: First Sequence

- Pembrolizumab 200mg IV on Day 1 (cycle = 21 days)

Administration Sequence: Second Sequence

• Gemcitabine 1000mg/m^2 IV on Days 1,8 (cycle = 21 days)
• Docetaxel 75mg/^2 IV on Days 1,8 (cycle = 21 days)
• Pemetrexed 500mg/m^2 IV on Day 1 (cycle -= 21 days)

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 35 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Masking Description: Open Label
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Chemotherapy Plus Pembrolizumab in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC) Previously Treated With PD-1 or PD-L1 Inhibitor: Big Ten Cancer Research Consortium BTCRC-LUN15-029
• Actual Study Start Date: March 20, 2017
• Actual Primary Completion Date: December 14, 2021
• Estimated Study Completion Date: February 2023

Arms and Interventions

Arm

Intervention/treatment

Experimental: Pembrolizumab 200mg IV every 21 days; Patients who have been treated with a PD-1 or PD-L1 inhibitor and experienced a PFS of ≥3 months will be enrolled within 6 weeks of last dose of PD-1 or PD-L1 inhibitor. On Day 1 of each 3-week cycle, subjects will first receive pembrolizumab at a dose of 200mg IV every three weeks in combination with chemotherapy. Partner chemotherapy will be either gemcitabine 1000mg/m^2 IV D1 and D8 every three weeks, docetaxel 75mg/m^2 IV D1 every three weeks, or pemetrexed 500mg/m^2 IV D1 every 3 weeks (pemetrexed for non-squamous histologies only). Subjects will continue to receive this combination until progression or intolerable toxicity.

Drug: Pembrolizumab; Pembrolizumab 200mg IV every 21 days + Physician's choice chemotherapy with one of the following every 21 days: Docetaxel 75mg/m2 IV; Pemetrexed 500mg/m2 IV (non-squamous only); Gemcitabine 1000mg/m2 IV on days 1 and 8; Other Names: Keytruda®; MK-3475

Outcome Measures

Primary Outcome Measures :

1. Progression Free Survival (PFS) [ Time Frame: Time of treatment start until the criteria for disease progression or death, up to a maximum of 28 months ]

   Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter(LD) of target lesions; Progressive Disease (PD): >= 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.

   PFS was defined as time from starting treatment to disease progression met by RECIST 1.1, start of additional anticancer therapy before progression, or death from any cause.

Secondary Outcome Measures :

1. Clinical Benefit Rate (CBR) [ Time Frame: Up to a maximum of 28 months ]

   Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter(LD) of target lesions; Progressive Disease (PD) >= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD.

   Per Immune-Related RECIST (irRECIST): Complete Response(irCR), Disappearance of all measurable and non-measurable lesions; Partial Response (irPR) >=30% decrease in tumor burden relative to baseline; Progressive Disease (irPD), >= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions confirmed by a consecutive assessment at least 4 week after first documentation; Stable Disease (irSD), not meeting criteria for irCR or irPR, in absence of irPD CBR is defined as any subject with SD for ≥ 3 months, PR or CR assessed via RECIST 1.1 and irRECIST.

2. Objective Response Rate (ORR) [ Time Frame: Up to a maximum of 28 months ]

   Per RECIST: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter(LD) of target lesions; Progressive Disease (PD) >= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD.

   Per irRECIST: Complete Response(irCR), Disappearance of all measurable and non-measurable lesions; Partial Response (irPR) >=30% decrease in tumor burden relative to baseline; Progressive Disease (irPD), >= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions confirmed by a consecutive assessment at least 4 week after first documentation; Stable Disease (irSD), not meeting criteria for irCR or irPR, in absence of irPD ORR is defined as the proportion of all subjects with confirmed PR or CR according to RECIST 1.1 and irRECIST, from the start of treatment until disease progression/recurrence

3. Overall Survival (OS) [ Time Frame: Time of treatment start until death or up to a maximum of 40 months ]
   Time from date of treatment start to date of death from any cause
4. Number of Participants With Adverse Events [ Time Frame: Adverse events were recorded from time of registration until 30 days after discontinuation of study drug(s) up to a maximum of 25 months. ]
   Toxicity will be graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 4
5. Progression Free Survival (PFS) by irRECIST [ Time Frame: Time of treatment start until the criteria for disease progression or death, up to a maximum of 28 months ]

   Per Immune-Related RECIST (irRECIST): Complete Response(irCR), Disappearance of all measurable and non-measurable lesions; Partial Reponse (irPR): >=30% decrease in in tumor burden relative to baseline; Progressive Disease (irPD), >= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions confirmed by a consecutive assessment at least 4 week after first documentation; Stable Disease (irSD), not meeting criteria for irCR or irPR, in absence of irPD.

   PFS is defined as time from the date of treatment start until the criteria for disease progression is met as defined by irRECIST or death occurs.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

Subjects must meet all of the following applicable inclusion criteria to participate in this study:

• Written informed consent and HIPAA authorization for release of protected health information.
• Age ≥ 18 years at the time of consent.
• Histological or cytological evidence of stage IV NSCLC (any histology)
• Subjects must have progressed on or after previous platinum-based chemotherapy. Chemotherapy may have previously been given with a PD-1 or PD-L1 inhibitor. Subjects must have also progressed on or after receiving any PD-1 or PD-L1 inhibitor (including pembrolizumab) as their most recent therapy and must have had at least a 3-month PFS on this therapy.
• Subjects must be enrolled on the trial within 6 weeks of their last infusion of PD-1 or PD-L1 inhibitor therapy.
• Subjects whose tumors harbor a mutation in EGFR exon 19 or 21 or have gene rearrangements in ALK or ROS1 must have already been treated with standard targeted therapies. NOTE: Subjects must also have progressed on or after platinum-containing combination chemotherapy.
• ECOG Performance Status of 0 or 1 within 28 days prior to registration for protocol therapy.
• Must be fit enough to receive next-line chemotherapy (either gemcitabine, docetaxel, or pemetrexed [non-squamous only]) according to the discretion of the treating physician.
• Adequate laboratory values obtained within 28 days prior to registration for protocol therapy.
• Women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test within 7 days prior to study registration and/or within 72 hours of first dose of study drugs. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Women of childbearing potential must be willing to use two methods of contraception or abstain from heterosexual activity from the point of registration through 120 days after the last dose of study drug.
• Male subjects capable of fathering a child must agree to use an adequate method of contraception starting with the first dose of the study drug through 120 days after the last dose of the study drug.

Exclusion Criteria:

Subjects meeting any of the criteria below may not participate in the study:

• 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.
• Active central nervous system (CNS) metastases. NOTE: Subjects who are symptomatic or have not undergone prior brain imaging must undergo a head computed tomography (CT) scan or brain MRI within 28 days prior to registration to exclude brain metastases.
• Treatment with any investigational agent within 28 days prior to registration for protocol therapy with the exception of PD-1 or PD-L1 inhibitors.
• No active second cancers with the exception of localized non-melanoma skin cancer, in-situ cervical or in-situ bladder cancer.
• Evidence of active autoimmune disease requiring systemic treatment within the past 90 days or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents.
• History of (non-infectious) pneumonitis requiring treatment with corticosteroids, evidence of interstitial lung disease or active, non-infectious pneumonitis.
• History of an immune-related toxicity requiring treatment with corticosteroids during prior PD-1/ PD-L1 inhibitor treatment.
• Diagnosis of immunodeficiency or is receiving chronic systemic corticosteroid therapy or other immunosuppressive therapy (excludes inhaled corticosteroids) within 7 days of study registration.
• History of psychiatric illness or social situations that would limit compliance with study requirements.
• Clinically active infection (≥ Grade 2) as judged by the site investigator.
• Known history of human immunodeficiency virus (HIV) infection or chronic hepatitis B or C. NOTE: HIV, HBV or HCV testing is not required.
• 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 site investigator.
• Known history of active TB (Bacillus Tuberculosis).
• History of hypersensitivity to pembrolizumab, docetaxel, gemcitabine, pemetrexed or any of their excipients.
• Has received a live vaccine within 30 days prior to planned start of study therapy.

Contacts and Locations

Locations

United States, Illinois

University of Illinois Cancer Center

Chicago, Illinois, United States, 60612

United States, Indiana

Indiana University Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, United States, 46202

United States, Iowa

University of Iowa Hospital Clinics

Iowa City, Iowa, United States, 52242

United States, Minnesota

University of Minnesota Medcical Center

Minneapolis, Minnesota, United States, 55455

United States, Wisconsin

University of Wisconsin

Madison, Wisconsin, United States, 53705

Sponsors and Collaborators

Greg Durm, MD

Merck Sharp & Dohme LLC

Big Ten Cancer Research Consortium

Investigators

• Study Chair: Greg Durm, M.D.; Big Ten Cancer Research Consortium

  Study Documents (Full-Text)

Documents provided by Greg Durm, MD, Big Ten Cancer Research Consortium:

Study Protocol and Statistical Analysis Plan  [PDF] November 7, 2019

More Information

Additional Information:

Big Ten Cancer Research Consortium Website 

• Responsible Party: Greg Durm, MD, Sponsor-Investigator, Big Ten Cancer Research Consortium
• ClinicalTrials.gov Identifier: NCT03083808
• Other Study ID Numbers: BTCRC-LUN15-029
• First Posted: March 20, 2017
• Results First Posted: June 28, 2022
• Last Update Posted: June 28, 2022
• Last Verified: June 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Greg Durm, MD, Big Ten Cancer Research Consortium:

PD-1; PD-L1 Inhibitor; Pembrolizumab; Docetaxel; Pemetrexed; Gemcitabine

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action