Clinical Trial: NCT04267848 - My Cancer Genome

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
Non-Squamous Non-Small Cell Lung Carcinoma

Recruiting Status:

Recruiting

Phase:

Phase 3

URL:

https://clinicaltrials.gov/show/NCT04267848

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 (ACCIO)

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

Interventions

Drug	Synonyms	Arms
Carboplatin	Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, Ribocarbo	Arm A (platinum doublet, observation)
Cisplatin	Abiplatin, 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, Platosin	Arm A (platinum doublet, observation)
Gemcitabine Hydrochloride	dFdCyd, Difluorodeoxycytidine Hydrochloride, FF 10832, FF-10832, FF10832, Gemcitabine HCI, Gemzar, LY-188011, LY188011	Arm A (platinum doublet, observation)
Paclitaxel	Anzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol Konzentrat	Arm A (platinum doublet, observation)
Pembrolizumab	Keytruda, Lambrolizumab, MK-3475, SCH 900475	Arm B (platinum doublet, sequential pembrolizumab)
Pemetrexed Disodium	Alimta, 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 Salt	Arm A (platinum doublet, observation)

Purpose

Detailed Description

      PRIMARY OBJECTIVES:

      I. To compare the disease free survival (DFS) and overall survival (OS) (dual primary
      endpoints) between combination 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 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 pembrolizumab with standard of care (Arm C)
      vs. sequential standard of care followed by 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 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 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 (tumor proportion score [TPS] >= 50% vs TPS < 50%) in patients with stage IB-IIIA
      non-small cell lung cancer.

      IV. To compare the DFS and OS between 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 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 + observation (Arm A).

      II. To compare patient reported QOL one year after randomization 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
      (Arm A).

      III. To compare patient-reported QOL at completion of chemotherapy 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. 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 with the addition of 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 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 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 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.

Trial Arms

Name	Type	Description	Interventions
Arm A (platinum doublet, observation)	Active Comparator	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.	Carboplatin Cisplatin Gemcitabine Hydrochloride Paclitaxel Pemetrexed Disodium
Arm B (platinum doublet, sequential pembrolizumab)	Experimental	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.	Carboplatin Cisplatin Gemcitabine Hydrochloride Paclitaxel Pembrolizumab Pemetrexed Disodium
Arm C (platinum doublet, combination pembrolizumab)	Experimental	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.	Carboplatin Cisplatin Gemcitabine Hydrochloride Paclitaxel Pembrolizumab Pemetrexed Disodium

Eligibility Criteria

        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 IB (>= 4 cm), II or IIIA non-small cell lung cancer (NSCLC)
             (squamous or non-squamous) 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

          -  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

          -  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:

          -  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

          -  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

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 (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 Outcome Measures

Measure:	DFS between combination pembrolizumab with standard of care versus (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
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:	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.

Measure:	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
Safety Issue:
Description:	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.

Details

Phase:	Phase 3
Primary Purpose:	Interventional
Overall Status:	Recruiting
Lead Sponsor:	National Cancer Institute (NCI)

Last Updated

August 25, 2021

Clinical Trials /

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