Testing the Addition of a Type of Drug Called Immunotherapy to the Usual Chemotherapy Treatment for Non-small Cell Lung Cancer, ALCHEMIST Chemo-IO Study

Overview

This phase III ALCHEMIST trial tests the addition of pembrolizumab to usual chemotherapy for the treatment of stage IIA, IIB IIIA or IIIB non-small cell lung cancer that has been removed by surgery. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as cisplatin, pemetrexed, carboplatin, gemcitabine hydrochloride, and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving pembrolizumab with usual chemotherapy may help increase survival times in patients with stage IIA, IIB IIIA or IIIB non-small cell lung cancer.

Full Title of Study: “Integration of Immunotherapy Into Adjuvant Therapy for Resected NSCLC: ALCHEMIST Chemo-IO (ACCIO)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: December 15, 2024

Detailed Description

PRIMARY OBJECTIVE: I. To compare the disease free survival (DFS) between Arm B versus (vs) Arm C in patients with stage IIA-IIIB (T3-4N2) non-small cell lung cancer. SECONDARY OBJECTIVES: I. To compare the overall survival (OS) between the two treatment arms in patients with stage IIA-IIIB (T3-4N2) non-small cell lung cancer. II. To compare the adverse event rates and drug discontinuation rates due to adverse events in patients with stage IIA-IIIB (T3-4N2) non-small cell lung cancer. III. To compare the adverse event (AE) rates for Arms B and C with A (prior to Update #7) and estimate the DFS and OS in Arm A. IV. To compare the DFS and OS in patients with stage IIA-IIIB (T3-4N2) non-small cell lung cancer that receive at least 2 cycles of initial adjuvant chemotherapy. QUALITY OF LIFE OBJECTIVES: I. To compare patient-reported quality of life (QOL) one year after randomization as assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-Core (C)30 between patients randomized to receive adjuvant chemotherapy followed by pembrolizumab (Arm B), and those randomized to receive adjuvant chemotherapy + pembrolizumab concomitantly (Arm C). II. To compare patient-reported QOL at completion of chemotherapy as assessed by the EORTC QLQ-C30 between patients randomized to receive adjuvant chemotherapy followed by pembrolizumab (Arm B) and those randomized to receive adjuvant chemotherapy + pembrolizumab concomitantly (Arm C). III. To present longitudinal trajectories by arm of patient-reported dyspnea and coughing as assessed by the EORTC QLQ-Lung Cancer (LC13). CORRELATIVE SCIENCE OBJECTIVES: I. To compare the DFS and OS in the PD-L1 subgroup of patients with PD-L1 expression status (>= 1% vs < 1%). II. To compare the DFS and OS by tumor mutational burden status (high vs. low) in patients with stage IIA-IIIB (T3-4N2) non-small cell lung cancer. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A (CLOSED AS OF UPDATE #7): INITIAL THERAPY: Patients receive 1 of 4 platinum doublet regimens* based on the treating physician's choice. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. CONTINUANCE THERAPY: Patients then undergo observation. ARM B: INITIAL THERAPY: Patients receive 1 of 4 platinum doublet regimens* based on the treating physician's choice. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. CONTINUANCE THERAPY: Patients then receive pembrolizumab intravenously (IV) over 25-40 minutes on day 1. Treatment repeats every 21 days for 17 cycles or every 6 weeks for 16 cycles (patients enrolled after 10/14/2020) in the absence of disease progression or unacceptable toxicity. ARM C: INITIAL THERAPY: Patients receive 1 of 4 platinum doublet regimens* based on the treating physician's choice and pembrolizumab IV over 25-40 minutes on day 1. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. CONTINUANCE THERAPY: Patients then receive pembrolizumab IV over 25-40 minutes on day 1. Treatment repeats every 21 days for 13 cycles or every 6 weeks for 12 cycles (patients enrolled after 10/14/2020) in the absence of disease progression or unacceptable toxicity. *ACCEPTABLE REGIMENS: DOUBLET I: Patients receive cisplatin IV over 1-2 hours and pemetrexed IV over 10 minutes on day 1 of each cycle. DOUBLET II: Patients receive carboplatin IV over 30 minutes and pemetrexed IV over 10 minutes on day 1 of each cycle. DOUBLET III: Patients receive cisplatin IV over 1-2 hours on day 1 of each cycle and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 of each cycle. DOUBLET IV: Patients receive carboplatin IV over 30 minutes and paclitaxel IV over 3 hours on day 1 of each cycle. After completion of study treatment, patients are followed up at 6 weeks, then every 3 months for 2 years from randomization, every 6 months for years 2-4, and then annually for up to 10 years from randomization.

Interventions

  • Drug: Carboplatin
    • Given IV
  • Drug: Cisplatin
    • Given IV
  • Drug: Gemcitabine Hydrochloride
    • Given IV
  • Other: Observation
    • Undergo observation
  • Drug: Paclitaxel
    • Given IV
  • Biological: Pembrolizumab
    • Given IV
  • Drug: Pemetrexed Disodium
    • Given IV
  • Other: Quality-of-Life Assessment
    • Ancillary studies
  • Other: Questionnaire Administration
    • Ancillary studies

Arms, Groups and Cohorts

  • Active Comparator: Arm A (platinum doublet, observation)
    • INITIAL THERAPY: Patients receive 1 of 4 platinum doublet regimens based on the treating physician’s choice. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. CONTINUANCE THERAPY: Patients then undergo observation. (CLOSED AS OF UPDATE #7)
  • Experimental: Arm B (platinum doublet, sequential pembrolizumab)
    • INITIAL THERAPY: Patients receive 1 of 4 platinum doublet regimens based on the treating physician’s choice. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. CONTINUANCE THERAPY: Patients then receive pembrolizumab IV over 25-40 minutes on day 1. Treatment repeats every 21 days for 17 cycles or every 6 weeks for 16 cycles (patients enrolled after 10/14/2020) in the absence of disease progression or unacceptable toxicity.
  • Experimental: Arm C (platinum doublet, combination pembrolizumab)
    • INITIAL THERAPY: Patients receive 1 of 4 platinum doublet regimens based on the treating physician’s choice and pembrolizumab IV over 25-40 minutes on day 1. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. CONTINUANCE THERAPY: Patients then receive pembrolizumab IV over 25-40 minutes on day 1. Treatment repeats every 21 days for 13 cycles or every 6 weeks for 12 cycles (patients enrolled after 10/14/2020) in the absence of disease progression or unacceptable toxicity.

Clinical Trial Outcome Measures

Primary Measures

  • Disease free survival (DFS)
    • Time Frame: From randomization to the first of either disease recurrence or death from any cause, assessed up to 5 years after accrual completion
    • Will be estimated using the Kaplan-Meier method, where the stratified log-rank test (using the central PD-L1 result for the PD-L1 expression status) will be used to compare the distributions across the treatment arms. DFS rates at 1 year, 2 years, and 5 years will also be reported, along with 95% confidence intervals. Univariable and multivariable Cox models stratified by the stratification factors (using the central PD-L1 result for the PD-L1 expression status) used in the randomization will be assessed as well.

Secondary Measures

  • Overall survival (OS)
    • Time Frame: From randomization to death from any cause, assessed up to 8 years after accrual completion
    • Will be estimated using the Kaplan-Meier method, where the stratified log-rank test (using the central PD-L1 result for the PD-L1 expression status) will be used to compare the distributions across the treatment arms. OS rates at 1 year, 2 years, and 5 years will also be reported, along with 95% confidence intervals. Univariable and multivariable Cox models stratified by the stratification factors (using the central PD-L1 result for the PD-L1 expression status) used in the randomization will be assessed as well.
  • Incidence of adverse events
    • Time Frame: Up to 10 years
    • The maximum grade for each type of adverse event will be summarized using Common Terminology Criteria for Adverse Events (CTCAE) version 5. The frequency and percentage of grade 3+ adverse events will be compared between the 2 experimental treatment arms and the control as well as between the two experimental arms. We will also compare the rate of drug discontinuation due to adverse events between the experimental treatment arms and control, and between the two experimental arms. Comparisons between arms will be made by using the Chi-square test. Analysis of the overall adverse event rates, as well as specific events of interest will involve Chi-square tests or Fisher’s exact tests.
  • DFS between each experimental pembrolizumab plus standard of care arms vs. standard of care
    • Time Frame: From randomization to the first of either disease recurrence or death from any cause, assessed up to 5 years after accrual completion
    • Assessed by PD-L1 expression status (tumor proportion score >= 50% vs. tumor proportion score < 50%). Univariable and multivariable Cox models stratified by the stratification factors used in the randomization will be used as the primary analytical method, where all baseline covariates will be considered in the univariable models and subsequently in the multivariable models based on the criteria for selection for the multivariable models.
  • OS between each experimental pembrolizumab plus standard of care arms vs. standard of care
    • Time Frame: From randomization to death from any cause, assessed up to 8 years after accrual completion
    • Assessed by PD-L1 expression status. Univariable and multivariable Cox models stratified by the stratification factors used in the randomization will be used as the primary analytical method, where all baseline covariates will be considered in the univariable models and subsequently in the multivariable models based on the criteria for selection for the multivariable models.

Participating in This Clinical Trial

Inclusion Criteria

  • Previously registered to A151216 (NCT02194738) – Central and/or local testing of EGFR with no EGFR exon 19 deletion or EGFR L858 R mutation (applicable to non-squamous patients only) – Central and/or local testing of ALK with no ALK rearrangement (failed testing is considered negative) (applicable to non-squamous patients only) – Central and/or local testing of PD-L1 immunohistochemistry (IHC) using one of the following assays: DAKO 22C3, DAKO 28-8, EIL3N or SP263 – Note: Local testing results of EGFR and ALK by a local Clinical Laboratory Improvement Act (CLIA) certified laboratory is acceptable. The report must indicate the result as well as the CLIA number of the laboratory that performed the assay. Local result of PD-L1 by DAKO 22C3, Dako 28-8, EIL3N or SP263 are acceptable for enrollment on A081801. Patients with local results for EGFR, ALK and PD-L1 still need to be registered to A151216 and follow all the submissions requirements but do NOT need to wait for the results to proceed to A081801 registration – Completely resected stage IIA, IIB IIIA or IIIB (T3-4N2) non-small cell lung cancer (NSCLC) (squamous or non-squamous) with negative margins (complete R0 resection). Patients will be staged according to the 8th edition of the American Joint Committee on Cancer (AJCC) Staging Manual, 2017 – Note: Patients with pathologic N2 disease, completely resected, are eligible. However, patients known to have N2 disease prior to surgery are not eligible; guidelines do not recommend up-front surgery for this population – Complete recovery from surgery. Registration to A081801 must be 30-77 days following surgery – No prior neoadjuvant or adjuvant therapy for current lung cancer diagnosis – No prior allogeneic tissue/solid organ transplant – No current pneumonitis or history of (non-infectious) pneumonitis that required steroids – Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial – Age >= 18 years – Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0-1 – No active auto-immune disease that has required systemic treatment within the last 2 years (e.g., disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid release therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment – Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required – No patients with a "currently active" second malignancy that is progressing or has required active treatment within the last 3 years. Participants with non-melanoma skin cancers or carcinoma in situ (e.g., breast carcinoma or cervical cancer in situ) that have undergone potentially curative therapy are eligible – No hypersensitivity (>= grade 3) to pembrolizumab and/or any of its excipients – No live vaccine within 30 days prior to registration. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed – No known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known hepatitis C virus (defined as HCV ribonucleic acid [RNA] [qualitative] is detected) infection – Absolute neutrophil count (ANC) >= 1,500/mm^3 – Platelet count >= 100,000/mm^3 – Hemoglobin >= 8 gm/dl – Calculated (Calc.) creatinine clearance >= 45 mL/min – Total bilirubin =< 1.5 x upper limit of normal (ULN) – Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) Exclusion Criteria:

  • Patients must NOT have uncontrolled intercurrent illness including, but not limited to, serious ongoing or active infection, symptomatic congestive heart failure, uncontrolled cardiac arrhythmia, unstable angina pectoris, that would limit compliance with study requirements

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • National Cancer Institute (NCI)
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Jacob M Sands, Principal Investigator, Alliance for Clinical Trials in Oncology

Clinical trials entries are delivered from the US National Institutes of Health and are not reviewed separately by this site. Please see the identifier information above for retrieving further details from the government database.

At TrialBulletin.com, we keep tabs on over 200,000 clinical trials in the US and abroad, using medical data supplied directly by the US National Institutes of Health. Please see the About and Contact page for details.