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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

NCT04267848

Description:

This phase III ALCHEMIST trial compares the addition of pembrolizumab to usual chemotherapy versus usual chemotherapy for the treatment of stage IB, II, or IIIA 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. Drugs used in chemotherapy, 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. The purpose of this trial is to find out if the addition of pembrolizumab to usual chemotherapy is better or worse than usual chemotherapy alone for non-small cell lung cancer.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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
  • Official Title: Integration of Immunotherapy Into Adjuvant Therapy for Resected NSCLC: ALCHEMIST Chemo-IO

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-00751
  • SECONDARY ID: NCI-2020-00751
  • SECONDARY ID: A081801
  • SECONDARY ID: A081801
  • SECONDARY ID: U10CA180821
  • NCT ID: NCT04267848

Conditions

  • Lung Non-Small Cell Carcinoma
  • Stage IB Lung Cancer AJCC v7
  • Stage II Lung Cancer AJCC v7
  • Stage IIA Lung Cancer AJCC v7
  • Stage IIB Lung Cancer AJCC v7
  • Stage IIIA Lung Cancer AJCC v7

Interventions

DrugSynonymsArms
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboArm A (platinum doublet, observation)
CisplatinAbiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone''s Chloride, Peyrone''s Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, PlatosinArm A (platinum doublet, observation)
GemcitabinedFdC, dFdCyd, DifluorodeoxycytidineArm A (platinum doublet, observation)
Gemcitabine HydrochloridedFdCyd, Difluorodeoxycytidine Hydrochloride, FF 10832, FF-10832, FF10832, Gemcitabine HCI, Gemzar, LY-188011, LY188011Arm A (platinum doublet, observation)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratArm A (platinum doublet, observation)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Arm B (platinum doublet, sequential pembrolizumab)
PemetrexedMTA, Multitargeted AntifolateArm A (platinum doublet, observation)
Pemetrexed DisodiumAlimta, Almita, LY231514, N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic Acid Disodium SaltArm A (platinum doublet, observation)

Purpose

This phase III trial compares the addition of pembrolizumab to usual chemotherapy versus usual chemotherapy for the treatment of stage IB, II, or IIIA 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. Drugs used in chemotherapy, 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. The purpose of this trial is to find out if the addition of pembrolizumab to usual chemotherapy is better or worse than usual chemotherapy alone for non-small cell lung cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To compare the disease free survival (DFS) and overall survival (OS) (dual primary
      endpoints) between combination MK-3475 (pembrolizumab) plus standard of care (Arm C) versus
      (vs.) standard of care (Arm A) in patients with stage IB-IIIA non-small cell lung cancer.

      II. To compare the DFS and OS (dual primary endpoints) between sequential MK-3475
      (pembrolizumab) following standard of care (Arm B) vs. standard of care (Arm A) followed by
      observation in patients with stage IB-IIIA non-small cell lung cancer.

      SECONDARY OBJECTIVES:

      I. To compare the DFS and OS between combination MK-3475 (pembrolizumab) with standard of
      care (Arm C) vs. sequential standard of care followed by MK-3475 (pembrolizumab) (Arm B) in
      patients with stage IB-IIIA non-small cell lung cancer.

      II. To compare the adverse event rates and drug discontinuation rates due to adverse events
      with the addition of MK-3475 (pembrolizumab) plus standard of care (combination and/or
      sequential; Arms B and C) vs. standard of care alone (Arm A) as well as Arm B versus Arm C in
      patients with stage IB-IIIA non-small cell lung cancer.

      III. To compare the DFS and OS between MK-3475 (pembrolizumab) plus standard of care
      (combination and/or sequential; Arms B and C) vs. standard of care alone (Arm A) by PD-L1
      expression status (>= 50% vs < 50%) in patients with stage IB-IIIA non-small cell lung
      cancer.

      IV. To compare the DFS and OS between MK-3475 (pembrolizumab) plus standard of care
      (combination and/or sequential; Arms B and C) vs. standard of care alone (Arm A) in patients
      with stage IB-IIIA 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 registration 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 MK-3475 (pembrolizumab) (Arm B), and those randomized to receive
      adjuvant chemotherapy + observation (Arm A).

      II. To compare patient reported QOL one year after registration as assessed by EORTC QLQ-C30
      between patients randomized to receive adjuvant chemotherapy + MK-3475 (pembrolizumab)
      concomitantly (Arm C) and those randomized to receive adjuvant chemotherapy + observation
      (Arm A).

      III. Compare patient-reported QOL 12 weeks after registration as assessed by the EORTC
      QLQ-C30 between patients randomized to receive adjuvant chemotherapy + pembrolizumab
      concomitantly (Arm C) and those randomized to receive adjuvant chemotherapy + observation or
      adjuvant chemotherapy followed by pembrolizumab (Arms A and B combined).

      IV. 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 with the addition of MK-3475 (pembrolizumab) (combination and/or
      sequential) to standard of care platinum-based adjuvant therapy (Arms B and C) vs standard of
      care (Arm A) in the PD-L1 subgroup of patients with PD-L1 expression status (>= 1% vs < 1%).

      II. To compare the DFS and OS with the addition of MK-3475 (pembrolizumab) (combination
      and/or sequential) to standard of care platinum-based adjuvant therapy (Arms B and C) vs.
      standard of care (Arm A) by tumor mutational burden status (high vs. low) in patients with
      stage IB-IIIA non-small cell lung cancer.

      III. To identify a cell-free deoxyribonucleic acid (cfDNA) marker associated with high-risk
      of recurrence and improved DFS and OS with the addition of MK-3475 (pembrolizumab) to
      standard adjuvant chemotherapy (Arms B and C).

      OUTLINE: Patients are randomized to 1 of 3 arms.

      ARM A:

      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 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 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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (platinum doublet, observation)Active ComparatorINITIAL 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.
  • Carboplatin
  • Cisplatin
  • Gemcitabine
  • Gemcitabine Hydrochloride
  • Paclitaxel
  • Pemetrexed
  • Pemetrexed Disodium
Arm B (platinum doublet, sequential pembrolizumab)ExperimentalINITIAL 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 in the absence of disease progression or unacceptable toxicity.
  • Carboplatin
  • Cisplatin
  • Gemcitabine
  • Gemcitabine Hydrochloride
  • Paclitaxel
  • Pembrolizumab
  • Pemetrexed
  • Pemetrexed Disodium
Arm C (platinum doublet, combination pembrolizumab)ExperimentalINITIAL 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 in the absence of disease progression or unacceptable toxicity.
  • Carboplatin
  • Cisplatin
  • Gemcitabine
  • Gemcitabine Hydrochloride
  • Paclitaxel
  • Pembrolizumab
  • Pemetrexed
  • Pemetrexed Disodium

Eligibility Criteria

        Inclusion Criteria:

          -  Previously registered to A151216

          -  Central and/or local testing of EGFR with no EGFR exon 19 deletion or EGFR L858 R
             mutation

          -  Central and/or local testing of ALK with no ALK rearrangement (failed testing is
             considered negative)

          -  Central and/or local testing of PD-L1 immunohistochemistry (IHC) using one of the
             following assays: DAKO 22C3, DAKO 28-8, 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, 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 IB (>= 4 cm), II or IIIA non-small cell lung cancer (NSCLC)
             with negative margins (complete R0 resection). Patients will be staged according to
             the 7th edition of the American Joint Committee on Cancer (AJCC) Staging Manual, 2010

               -  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

          -  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

          -  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

          -  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

          -  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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method, where the stratified log-rank test 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.

Secondary Outcome Measures

Measure:DFS between combination pembrolizumab with standard of care vs. sequential pembrolizumab
Time Frame:From randomization to the first of either disease recurrence or death from any cause, assessed up to 5 years after accrual completion
Safety Issue:
Description:
Measure:OS between combination pembrolizumab with standard of care vs. sequential pembrolizumab
Time Frame:From randomization to death from any cause, assessed up to 8 years after accrual completion
Safety Issue:
Description:
Measure:Incidence of adverse events
Time Frame:Up to 10 years
Safety Issue:
Description: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.
Measure:DFS between each experimental pembrolizumab plus standard of care arms vs. standard of care by PD-L1 expression status
Time Frame:From randomization to the first of either disease recurrence or death from any cause, assessed up to 5 years after accrual completion
Safety Issue:
Description: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.
Measure:OS between each experimental pembrolizumab plus standard of care arms vs. standard of care by PD-L1 expression status
Time Frame:From randomization to death from any cause, assessed up to 8 years after accrual completion
Safety Issue:
Description: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.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

February 12, 2020