Clinical Trials /

CHIO3 Trial: CHemotherapy Combined With Immune Checkpoint Inhibitor for Operable Stage IIIA/B Non-Small Cell Lung Cancer

NCT04062708

Description:

This is a single arm, phase II trial of combined neoadjuvant platinum doublet chemotherapy plus durvalumab followed by surgery, postoperative radiation and adjuvant durvalumab for 13 cycles for patients with potentially resectable stage IIIA and IIIB (T1-3, N2) NSCLC (per the 8th International Association for the Study of Lung Cancer classification). The primary objective of this study is to increase N2 nodal clearance (N2NC) to 50% or greater for combined platinum doublet chemotherapy with durvalumab induction therapy from historical rate of 30% for platinum doublet chemotherapy alone in patients with potentially resectable stage IIIA/B (N2) NSCLC.

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

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: CHIO3 Trial: CHemotherapy Combined With Immune Checkpoint Inhibitor for Operable Stage IIIA/B Non-Small Cell Lung Cancer
  • Official Title: CHIO3 Trial: CHemotherapy Combined With Immune Checkpoint Inhibitor for Operable Stage IIIA/B Non-Small Cell Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: AFT-46
  • NCT ID: NCT04062708

Conditions

  • Stage IIIA Non-small Cell Lung Cancer
  • Stage IIIB Non-small Cell Lung Cancer

Interventions

DrugSynonymsArms
DurvalumabImfinziTreatment

Purpose

This is a single arm, phase II trial of combined neoadjuvant platinum doublet chemotherapy plus durvalumab followed by surgery, postoperative radiation and adjuvant durvalumab for 13 cycles for patients with potentially resectable stage IIIA and IIIB (T1-3, N2) NSCLC (per the 8th International Association for the Study of Lung Cancer classification). The primary objective of this study is to increase N2 nodal clearance (N2NC) to 50% or greater for combined platinum doublet chemotherapy with durvalumab induction therapy from historical rate of 30% for platinum doublet chemotherapy alone in patients with potentially resectable stage IIIA/B (N2) NSCLC.

Detailed Description

      In the preoperative period, patients who have undergone adequate mediastinal evaluation and
      are considered operable will be treated with durvalumab 1125 mg IV every 3 weeks (Q3W) in
      combination with platinum doublet chemotherapy (cisplatin with pemetrexed or docetaxel,
      depending upon histology).

      Patients will undergo postoperative radiation (54Gy) within 4-10 weeks after surgery (unless
      single station N2 at registration with resultant ypT0N0 after neoadjuvant therapy).

      One to 6 weeks after completion of radiation, patients will receive adjuvant durvalumab 1500
      mg IV every 4weeks (Q4W) for 1 year.

      Patients who do not have surgery due to refusal, physician decision, or local and distant
      progression will have to discontinue study treatment.

      All participants will have imaging assessment prior to surgery after Cycle 2 (Week 6) and
      after Cycle 4 (Weeks 13 15). Patients will undergo potentially curable surgery as per
      standard of care.

      Patients will undergo imaging assessment every 12 weeks after surgery for 2 years, then every
      6 months for 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
TreatmentExperimentalCombined neoadjuvant platinum doublet chemotherapy plus durvalumab followed by surgery, postoperative radiation and adjuvant durvalumab for 13 cycles.
  • Durvalumab

Eligibility Criteria

        Operability Criteria:

          1. ECOG Performance Status 0-1.

          2. Absence of major associated comorbidities that increase the surgery risk to an
             unacceptable level.

          3. Pulmonary function capacity capable of tolerating the proposed lung resection. FEV1 at
             least 2 L. If less than 2 L, the predicted postoperative forced expiratory volume in 1
             second (FEV1) must be >0.8 L or be >35% of the predicted value. Postoperative
             predicted DLCO ≥35% is required.

        Inclusion Criteria:

          1. Patients who are at least 18 years of age.

          2. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.

          3. Life expectancy of at least 12 weeks.

          4. Patients with potentially resectable IIIA/B (T1-3, N2) NSCLC (per the 8th
             International Association for the Study of Lung Cancer classification) who are
             candidates for surgery with intent of R0 resection. Invasive T3 disease (eg, phrenic
             nerve, pericardium, chest wall other than Pancoast superior sulcus) may be included if
             the surgeon and study team deem it to be resectable. T4 disease per AJCC 8th edition
             staging system is excluded given the lack of benefit of surgery in T4N2.

          5. Patients must be evaluated by a thoracic surgeon within 4 weeks of registration.

          6. Operability is defined as having adequate pulmonary, cardiac, renal, nutritional,
             musculoskeletal, neurologic, and cognitive capacity to undergo major pulmonary
             resection with acceptable morbidity and mortality.

          7. N2 nodes must be discrete (ie, not invading surrounding structures) and less than 3 cm
             in maximum diameter.

          8. Measurable disease according to Response Evaluation Criteria in Solid Tumors version
             1.1 (RECIST v1.1).

          9. Pathologically proven N2 disease within 4 weeks of registration. PET/CT positivity in
             the ipsilateral mediastinal nodes will not be sufficient to establish N2 nodal status.
             Mediastinal lymph node sampling biopsy is required pre-operatively by at least one of
             the following:

               -  Endobronchial Ultrasound Transbronchial Needle Aspiration (EBUS-TBNA);

               -  Mediastinoscopy;

               -  Mediastinotomy (Chamberlain procedure);

               -  Endoscopic ultrasound guided node aspiration (EUS);

               -  Video-assisted thoracoscopy; OR

               -  Fine needle aspiration by image guidance.

               -  Endobronchial ultrasound (EBUS) or mediastinoscopy or other tissue sampling (at
                  least 2 stations must be biopsied, with at least one station positive for N2
                  disease). If there are any mediastinal nodes suspicious by CT (>1.5 cm) or PET in
                  N3 stations, they must be biopsied. If biopsy proven involvement in an N3
                  station, the patient is excluded.

         10. Mediastinal nodal biopsy or aspiration can only be omitted in the special circumstance
             in which ALL of the following are true:

               -  The tumor is left sided;

               -  The only mediastinal nodal involvement is a node visible in the AP (level 5)
                  region on CT scan;

               -  Distinct primary tumor separate from the nodes; AND

               -  Biopsy proven non-small cell histology from the primary tumor.

         11. No prior history of thoracic radiation.

         12. Organ and marrow function definitions (example below)

               -  leukocytes ≥3,000/mcL

               -  absolute neutrophil count ≥1,500/mcL

               -  platelets ≥100,000/mcL

               -  Hemoglobin >9.0 g/dL

               -  total bilirubin within normal institutional limits

               -  AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal

               -  creatinine within normal institutional limits OR

               -  creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels
                  above institutional normal.

         13. Patients are capable of giving informed consent and/or have an acceptable surrogate
             capable of giving consent on the subject's behalf.

         14. Nonpregnant and non-nursing. The effect of durvalumab on the fetus is unknown.

         15. Women of childbearing potential (WOCBP) must be willing to use 2 methods of birth
             control or be surgically sterile, or abstain from heterosexual activity for the course
             of the study through 3 months after the last dose of study medication. Patients of
             childbearing potential are those who have not been surgically sterilized or have not
             been free of menses >1 year.

         16. Evidence of postmenopausal status or negative urinary or serum pregnancy test for
             female premenopausal patients. Women will be considered postmenopausal if they have
             been amenorrheic for 12 months without an alternative medical cause. The following
             age-specific requirements apply:

               -  Women <50 years of age would be considered postmenopausal if they have been
                  amenorrheic for 12 months or more following cessation of exogenous hormonal
                  treatments and if they have luteinizing hormone and follicle-stimulating hormone
                  levels in the postmenopausal range for the institution or underwent surgical
                  sterilization (bilateral oophorectomy or hysterectomy).

               -  Women ≥50 years of age would be considered postmenopausal if they have been
                  amenorrheic for 12 months or more following cessation of all exogenous hormonal
                  treatments, had radiation-induced menopause with last menses >1 year ago, had
                  chemotherapy-induced menopause with last menses >1 year ago, or underwent
                  surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or
                  hysterectomy).

         17. Patient is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits and examinations including follow
             up.

         18. Male patients must agree to use an adequate method of contraception starting with the
             first dose of study therapy through 12 weeks after the last dose of study therapy.

        Exclusion Criteria:

          1. Any prior treatment for NSCLC.

          2. Prior thoracic radiation.

          3. Patients with ≥Grade 2 peripheral neuropathy.

          4. Any active or history of autoimmune disease (including any history of inflammatory
             bowel disease) or history of a syndrome that required systemic steroids or
             immunosuppressive medications, except for patients with vitiligo or resolved childhood
             asthma/atopy.

          5. Patients requiring systemic treatment with either corticosteroids (>10 mg daily
             prednisone equivalents) or other immunosuppressive medications within 14 days of study
             drug administration. Inhaled or topical steroids and adrenal replacement doses <10 mg
             daily prednisone equivalents are permitted in the absence of active autoimmune
             disease.

          6. Patients with previous malignancies (except nonmelanoma skin cancers, in situ bladder,
             gastric, breast, colon or cervical cancers/dysplasia) are excluded unless a complete
             remission was achieved at least 2 years prior to study entry and no additional therapy
             is required or anticipated to be required during the study period.

          7. History of solid organ transplant.

          8. N3 nodal disease.

          9. Mixed small cell/NSCLC will be excluded.

         10. Pregnant or breastfeeding.

         11. History of allogenic organ transplantation.

         12. Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [eg, colitis or Crohn's disease], active diverticulitis
             with the exception of diverticulosis, systemic lupus erythematosus, Sarcoidosis
             syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease,
             rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to
             this criterion:

               -  Patients with vitiligo or alopecia.

               -  Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone
                  replacement.

               -  Any chronic skin condition that does not require systemic therapy.

               -  Patients without active disease in the last 5 years may be included but only
                  after consultation with the study physician.

               -  Patients with celiac disease controlled by diet alone.

         13. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
             angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
             gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
             situations that would limit compliance with study requirement, substantially increase
             risk of incurring AEs or compromise the ability of the patient to give written
             informed consent.

         14. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms
             calculated.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:N2 nodal clearance (N2NC)
Time Frame:5 years
Safety Issue:
Description:To increase N2 nodal clearance (N2NC) to 50% or greater for combined platinum doublet chemotherapy with durvalumab induction from an historical rate of 30% for platinum doublet chemotherapy alone in patients with potentially resectable stage IIIA/B (N2) NSCLC.

Secondary Outcome Measures

Measure:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame:5 years
Safety Issue:
Description:To evaluate the safety and tolerability of neoadjuvant platinum doublet chemotherapy and durvalumab followed by surgery followed by adjuvant radiation and durvalumab.
Measure:Radiographic response rate
Time Frame:5 years
Safety Issue:
Description:To assess the radiographic response rate of neoadjuvant platinum doublet chemotherapy and durvalumab.
Measure:Rate of major pathologic response and pathologic complete response
Time Frame:16 weeks
Safety Issue:
Description:To evaluate the rate of major pathologic response and pathologic complete response in the resected primary tumor and lymph nodes following neoadjuvant combination therapy.
Measure:Evaluate event free survival (EFS)
Time Frame:5 years
Safety Issue:
Description:EFS evaluated from the time of registration to one of the following events, whichever comes first: a) radiographic disease progression, b) local progression as defined by lymph node progression precluding surgery, c) inability to resect the tumor, d) local or distant recurrence, e) death due to any cause.
Measure:Overall survival rate
Time Frame:5 years
Safety Issue:
Description:To evaluate overall survival rate from the time of registration
Measure:Rate of complete resection.
Time Frame:16 weeks
Safety Issue:
Description:To assess the rate of complete resection.
Measure:Post-operative complications
Time Frame:Within 30 days of surgery
Safety Issue:
Description:To assess post-operative complications

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Alliance Foundation Trials, LLC.

Trial Keywords

  • Stage IIIA/IIIB (T1-3,N2) Non-Small Cell Lung Cancer (NSCLC)

Last Updated