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Adjuvant Treatment With Cisplatin-based Chemotherapy Plus Concomitant Atezolizumab in Patients With Stage I (Tumors ≥ 4cm), IIA, IIB, and Select IIIA [T3N1, T4N0-1] Resected Non-small Cell Lung Cancer (NSCLC) and the Clearance of Circulating Tumor DNA (ctDNA)

NCT04367311

Description:

The vast majority of patients with stage I (tumors ≥ 4cm), IIA, IIB (and select IIIA) NSCLC are managed with upfront surgery, followed by adjuvant chemotherapy. However, relapse rates remain high and are primarily due to distant, metastatic disease. Previous meta-analysis evaluating the use of neo-adjuvant chemotherapy and adjuvant chemotherapy demonstrate a similar impact on improved disease free survival (DFS) and overall survival (OS). The role of checkpoint inhibitors has been proven to be effective in the treatment of patients with advanced NSCLC, regardless of histology and PD-L1 expression. Results from trials evaluating the use of checkpoint inhibitors alone or in combination with chemotherapy in the neoadjuvant setting for early stage disease are promising. However, there are no trials evaluating the role of concomitant chemotherapy and checkpoint inhibitors in the adjuvant setting. In addition, emerging data supports the use of ctDNA as a promising biomarker for early detection of minimal residual disease and have indicated that the presence of detectable ctDNA after surgery for localized lung cancer is correlated with a 90-100% chance for disease recurrence. Therefore, we propose this current study assessing concomitant chemotherapy plus Atezolizumab in the adjuvant setting for patients with stage I (tumors ≥ 4cm), IIA, IIB (and select IIIA) NSCLC who have detectable ctDNA after surgery. The clearance of ctDNA will serve as a surrogate for long term DFS and OS in this patient population.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Adjuvant Treatment With Cisplatin-based Chemotherapy Plus Concomitant Atezolizumab in Patients With Stage I (Tumors ≥ 4cm), IIA, IIB, and Select IIIA [T3N1, T4N0-1] Resected Non-small Cell Lung Cancer (NSCLC) and the Clearance of Circulating Tumor DNA (ctDNA)
  • Official Title: A Phase II Study of Adjuvant Treatment With Cisplatin-based Chemotherapy Plus Concomitant Atezolizumab in Patients With Stage I (Tumors ≥ 4cm), IIA, IIB, and Select IIIA [T3N1, T4N0-1] Resected Non-small Cell Lung Cancer (NSCLC) and the Clearance of Circulating Tumor DNA (ctDNA) Big Ten Cancer Research Consortium BTCRC-LUN19-396

Clinical Trial IDs

  • ORG STUDY ID: BTCRC-LUN19-396
  • NCT ID: NCT04367311

Conditions

  • Lung Cancer
  • NSCLC

Interventions

DrugSynonymsArms
AtezolizumabNSC: Non-squamous cell tumors
DocetaxelNSC: Non-squamous cell tumors
CisplatinNSC: Non-squamous cell tumors
PemetrexedSC: Squamous cell tumors

Purpose

The vast majority of patients with stage I (tumors ≥ 4cm), IIA, IIB (and select IIIA) NSCLC are managed with upfront surgery, followed by adjuvant chemotherapy. However, relapse rates remain high and are primarily due to distant, metastatic disease. Previous meta-analysis evaluating the use of neo-adjuvant chemotherapy and adjuvant chemotherapy demonstrate a similar impact on improved disease free survival (DFS) and overall survival (OS). The role of checkpoint inhibitors has been proven to be effective in the treatment of patients with advanced NSCLC, regardless of histology and PD-L1 expression. Results from trials evaluating the use of checkpoint inhibitors alone or in combination with chemotherapy in the neoadjuvant setting for early stage disease are promising. However, there are no trials evaluating the role of concomitant chemotherapy and checkpoint inhibitors in the adjuvant setting. In addition, emerging data supports the use of ctDNA as a promising biomarker for early detection of minimal residual disease and have indicated that the presence of detectable ctDNA after surgery for localized lung cancer is correlated with a 90-100% chance for disease recurrence. Therefore, we propose this current study assessing concomitant chemotherapy plus Atezolizumab in the adjuvant setting for patients with stage I (tumors ≥ 4cm), IIA, IIB (and select IIIA) NSCLC who have detectable ctDNA after surgery. The clearance of ctDNA will serve as a surrogate for long term DFS and OS in this patient population.

Trial Arms

NameTypeDescriptionInterventions
NSC: Non-squamous cell tumorsExperimentalAtezolizumab 1200mg, Docetaxel 60-75 mg/m^2, Cisplatin 60-75 mg/m^2
  • Atezolizumab
  • Docetaxel
  • Cisplatin
SC: Squamous cell tumorsExperimentalAtezolizumab 1200mg, Pemetrexed 500 mg/m^2, Cisplatin 60-75 mg/m^2
  • Atezolizumab
  • Cisplatin
  • Pemetrexed

Eligibility Criteria

        Inclusion Criteria:

          -  Written informed consent and HIPAA authorization for release of personal health
             information. NOTE: HIPAA authorization may be included in the informed consent or
             obtained separately.

          -  Age >= 18 years at the time of consent.

          -  ECOG Performance Status of 0-1 within 28 days prior to registration.

          -  Patients must have undergone complete surgical resection of their stage I (tumors >=
             4cm), IIA, IIB, and select IIIA (T3N1, T4N0-1) NSCLC according to the AJCC 8th edition
             with negative margins (R0).

          -  Squamous or non-squamous NSCLC histology. Cancers with a histology of "adenosquamous"
             are considered a type of adenocarcinoma and thus "non-squamous histology".

          -  Surgery for this lung cancer must be completed <= 60 days prior to starting treatment.

          -  Must have tissue available to perform prospective correlative testing. Tissue block is
             preferred but 10-15 unstained slides (5 μm thick) are also acceptable. If prior PD-L1
             results with Dako 22C3 antibody are not available, an additional 5 unstained slides (4
             μm thick) must be submitted.

          -  Demonstrate adequate organ function as defined in the protocol; all screening labs to
             be obtained within 28 days prior to registration.

          -  Females of childbearing potential must have a negative serum pregnancy test within 7
             days prior to registration NOTE: Females are considered of childbearing potential
             unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal
             ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least
             12 consecutive months

          -  For women of childbearing potential: agreement to remain abstinent (refrain from
             heterosexual intercourse) or use two non-hormonal methods of contraception, including
             at least one method with a failure rate of < 1% per year, during the treatment period
             and for 5 months after treatment discontinuation.

               -  Examples of non-hormonal contraceptive methods with a failure rate of < 1% per
                  year include bilateral tubal ligation, male sterilization, hormonal
                  contraceptives that inhibit ovulation, hormone-releasing intrauterine devices,
                  and copper intrauterine devices. Must use "estrogen-free" hormonal method if this
                  is chosen contraception method.

               -  A barrier method may be used as the second contraceptive method. The reliability
                  of sexual abstinence should be evaluated in relation to the duration of the
                  clinical trial and the preferred and usual lifestyle of the patient. Periodic
                  abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods)
                  and withdrawal are not acceptable methods of contraception.

          -  Contraception method must begin starting from the time of informed consent until 5
             months after treatment discontinuation.

          -  For men: Agreement to remain abstinent (refrain from heterosexual intercourse) or use
             a condom, and agreement to refrain from donating sperm, as defined below:

               -  With female partners of childbearing potential or pregnant female partners, men
                  must remain abstinent or use a condom during the treatment period and for 5
                  months after the last dose of study treatment to avoid exposing the embryo. Men
                  must refrain from donating sperm during this same period.

               -  The reliability of sexual abstinence should be evaluated in relation to the
                  duration of the clinical trial and the preferred and usual lifestyle of the
                  patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
                  post-ovulation methods) and withdrawal are not acceptable methods of
                  contraception.

          -  As determined by the enrolling physician or protocol designee, ability of the subject
             to understand and comply with study procedures for the entire length of the study

        Exclusion Criteria:

          -  Tumors that have any component of small cell or large cell neuroendocrine histology
             are NOT eligible.

          -  Tumors that are known to harbor EGFR mutations or ALK re-arrangements are NOT
             eligible.

          -  Prior chemotherapy, radiation therapy, or immunotherapy is NOT allowed for the
             treatment of this lung cancer.

          -  Prior chemotherapy and/or radiation therapy is permissible for the treatment of other
             previous cancers, but must have been completed at least 3 months prior to registration
             for this trial.

          -  Other active cancers.

          -  Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent
             directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40,
             CD137).

          -  Has received a live vaccine within 30 days prior to the first dose of study drug.
             Examples of live vaccines include, but are not limited to, the following: measles,
             mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
             Calmette-Guérin (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.

          -  Is currently participating in or has participated in a study of an investigational
             agent or has used an investigational device within 4 weeks prior to the first dose of
             study treatment.

        Note: Participants who have entered the follow-up phase of an investigational study may
        participate as long as it has been 4 weeks after the last dose of the previous
        investigational agent.

          -  Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
             (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
             immunosuppressive therapy within 1 week prior to registration.

          -  Has severe hypersensitivity (>= Grade 3) to atezolizumab and/or any of its excipients.

          -  Has active or history of autoimmune disease or immune deficiency that includes but is
             not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
             antibody syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré
             syndrome, or multiple sclerosis.

          -  Known interstitial lung disease that is symptomatic or may interfere with detection or
             management of suspected drug-related pulmonary toxicity are not permitted.

          -  Has a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis.

          -  Has a severe infection within 4 weeks prior to initiation of study treatment,
             including but not limited to hospitalization for complications of infection,
             bacteremia, or severe pneumonia.

          -  Has a known history of Human Immunodeficiency Virus (HIV). Note: HIV testing is not
             required.

          -  Has a known history of Hepatitis B or known active Hepatitis C virus infection. Note:
             If Hepatitis B and Hepatitis C status is unknown, testing is required:

               -  Subject must have negative total hepatitis B core antibody (HBcAb) test at
                  screening, or positive total HBcAb test followed by a negative hepatitis B virus
                  (HBV) DNA test at screening. The HBV DNA test will be performed only for patients
                  who have a positive total HBcAb test.

               -  Subject must have negative hepatitis C virus (HCV) antibody test at screening, or
                  positive HCV antibody test followed by a negative HCV RNA test at screening. The
                  HCV RNA test will be performed only for patients who have a positive HCV antibody
                  test. A positive HCV RNA test is sufficient to diagnose active HCV infection in
                  the absence of an HCV antibody test.

          -  Has a known history of active TB (Bacillus Tuberculosis).

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the study, interfere with the subject's
             participation for the full duration of the study, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator.

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

          -  Is pregnant or breastfeeding or expecting to conceive or father children within the
             projected duration of the study, starting with the screening visit through 5 months
             after the last dose of study drug.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of patients with undetectable ctDNA after 4 cycles of adjuvant chemotherapy + Atezolizumab plus up to 13 additional cycles of Atezolizumab in patients with stage I (tumors ≥ 4cm), IIA, IIB, and select IIIA [T3N1, T4N0-1]
Time Frame:Up to 17 cycles (13 months)
Safety Issue:
Description:To estimate the percentage of patients with undetectable circulating tumor DNA (ctDNA) after 4 cycles of adjuvant chemotherapy + Atezolizumab plus up to 13 additional cycles of Atezolizumab in patients with stage I (tumors ≥ 4cm), IIA, IIB, and select IIIA [T3N1, T4N0-1] NSCLC who have detectable ctDNA after surgery, but prior to adjuvant therapy. At each time point, ctDNA detection status (detectable or not detectable) will be determined by CAPP-seq using the Monte Carlo-based ctDNA detection index cutoff point of < 0.05, as described by Newman et al [53, 54]. If ctDNA detection index is > 0.05, ctDNA will be classified as not detected at that time point, whereas if < 0.05 then it will be classified as detected.

Secondary Outcome Measures

Measure:Percentage of patients with clearance of ctDNA after 4 cycles of adjuvant chemotherapy + Atezolizumab
Time Frame:4 cycles (3 months)
Safety Issue:
Description:To estimate the percentage of patients with clearance of ctDNA after 4 cycles of adjuvant chemotherapy + Atezolizumab in patients with stage I (tumors ≥ 4 cm), IIA, IIB, and select IIIA [T3N1, T4N0-1] NSCLC who have undergone surgical resection with detectable ctDNA after surgery.
Measure:Percentage of patients with clearance of ctDNA after 8 cycles (4 cycles of adjuvant chemotherapy + Atezolizumab plus 4 additional cycles of Atezolizumab)
Time Frame:8 cycles (6 months)
Safety Issue:
Description:To estimate the percentage of patients with clearance of ctDNA after 8 cycles (4 cycles of adjuvant chemotherapy + Atezolizumab plus 4 additional cycles of Atezolizumab) in patients with stage I (tumors ≥ 4 cm), IIA, IIB, and select IIIA [T3N1, T4N0-1] NSCLC who have undergone surgical resection with detectable ctDNA after surgery.
Measure:Percentage of patients with clearance of ctDNA after 12 cycles (4 cycles of adjuvant chemotherapy + Atezolizumab plus 8 additional cycles of Atezolizumab)
Time Frame:12 cycles (9 months)
Safety Issue:
Description:To estimate the percentage of patients with clearance of ctDNA after 12 cycles (4 cycles of adjuvant chemotherapy + Atezolizumab plus 8 additional cycles of Atezolizumab) in patients with stage I (tumors ≥ 4 cm), IIA, IIB, and select IIIA [T3N1, T4N0-1] NSCLC who have undergone surgical resection with detectable ctDNA after surgery.
Measure:Percentage of patients with clearance of ctDNA during or after adjuvant chemotherapy + Atezolizumab followed by Atezolizumab for up to 13 additional cycles who had no detectable ctDNA after surgery
Time Frame:Up to 17 cycles (13 months)
Safety Issue:
Description:To estimate the percentage of patients with clearance of ctDNA during or after adjuvant chemotherapy + Atezolizumab followed by Atezolizumab for up to 13 additional cycles who had no detectable ctDNA after surgery
Measure:Percentage of pts with clearance of ctDNA after 4 cycles of adj. chemotherapy + Atezolizumab plus up to 13 additional cycles of Atezolizumab in pts with stage I (tumors ≥ 4 cm), IIA, IIB, and select IIIA [T3N1, T4N0-1] NSCLC who have undergone resection
Time Frame:Up to 17 cycles (13 months)
Safety Issue:
Description:To estimate the percentage of patients with clearance of ctDNA after 4 cycles of adjuvant chemotherapy + Atezolizumab plus up to 13 additional cycles of Atezolizumab in patients with stage I (tumors ≥ 4 cm), IIA, IIB, and select IIIA [T3N1, T4N0-1] NSCLC who have undergone surgical resection, regardless of ctDNA status after surgery
Measure:1 year Disease Free Survival (DFS) in all patients
Time Frame:1 year
Safety Issue:
Description:To estimate the 1 year Disease Free Survival (DFS) in all patients treated on study
Measure:1 year Disease Free Survival (DFS) in patients with no detectable ctDNA after 4 cycles of adjuvant chemotherapy + Atezolizumab who had detectable ctDNA after surgery.
Time Frame:1 year
Safety Issue:
Description:To estimate the 1 year Disease Free Survival (DFS) in patients with no detectable ctDNA after 4 cycles of adjuvant chemotherapy + Atezolizumab who had detectable ctDNA after surgery.
Measure:1 year Disease Free Survival (DFS) in patients with detectable ctDNA after 1 year of adjuvant therapy on study
Time Frame:1 year
Safety Issue:
Description:1 year Disease Free Survival (DFS) in patients with detectable ctDNA after 1 year of adjuvant therapy on study

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Nasser Hanna

Last Updated

April 28, 2020