Clinical Trials /

Personalized Escalation of Consolidation Treatment Following Chemoradiotherapy and Immunotherapy in Stage III NSCLC in Stage III NSCLC

NCT04585490

Description:

The purpose of this study is to test whether or not number of circulating cancer cells detected in the blood can be decreased the by combining the standard treatment (durvalumab) with additional chemotherapy

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

Not yet recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Personalized Escalation of Consolidation Treatment Following Chemoradiotherapy and Immunotherapy in Stage III NSCLC in Stage III NSCLC
  • Official Title: Personalized Escalation of Consolidation Treatment Following Chemoradiotherapy and Immunotherapy in Stage III NSCLC

Clinical Trial IDs

  • ORG STUDY ID: IRB-54807
  • SECONDARY ID: LUN0114
  • NCT ID: NCT04585490

Conditions

  • Non Small Cell Lung Cancer
  • NSCLC, Stage III
  • Nsclc

Interventions

DrugSynonymsArms
DurvalumabImfinzi, MEDI-4736, MEDI4736Cohort 1 minimal residual disease positive (MRD+)
CarboplatinCarboplat, Carbosol, Carboplatino, cis-diammine(cyclobutane-1,1-dicarboxylato)platinumCohort 1 minimal residual disease positive (MRD+)
PemetrexedAlimta, MTA, LY231514, L-glutamic acid, N-(4-(2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo(2,3-d)pyrimidin-5-yl)ethyl)benzoyl)Cohort 1 minimal residual disease positive (MRD+)
PaclitaxelPraxelCohort 1 minimal residual disease positive (MRD+)
Cisplatinplatinum diamminodichloride, Abiplatin, Cismaplat, cis-platinum, Platinex, platinum, diaminedichloro-, cis- (8CI)Cohort 1 minimal residual disease positive (MRD+)

Purpose

The purpose of this study is to test whether or not number of circulating cancer cells detected in the blood can be decreased the by combining the standard treatment (durvalumab) with additional chemotherapy

Detailed Description

      Primary objective is to measure the change in the levels of circulating tumor DNA (ctDNA) in
      Cohort 1 (MRD+) due to the addition of platinum doublet chemotherapy in subjects with stage
      III unresectable disease with positive DNA treated with consolidation chemotherapy and
      immunotherapy.

      Secondary Objectives:

        -  To determine the proportion of subjects in Cohort 1 MRD+ for whom ctDNA becomes
           undetectable after chemotherapy

        -  To describe overall survival (OS) of subjects with baseline detectable ctDNA (Cohort 1
           MRD+) vs baseline undetectable ctDNA (Cohort 2 MRD ) ·To describe progression free
           survival (PFS) between subjects with baseline detectable (Cohort 1 MRD+) vs baseline
           undetectable ctDNA (Cohort 2 MRD ) ·To describe the frequency and severity of toxicity
           of consolidation durvalumab plus chemotherapy
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1 minimal residual disease positive (MRD+)ExperimentalSubjects with detectable ctDNA will receive 4 cycles of platinum doublet chemotherapy [carboplatin/pemetrexed] and durvalumab (1500 mg IV every 21 days, for 1 year), except subjects with squamous cell carcinoma histology will receive carboplatin/paclitaxel. Subjects will be evaluated with PET/CT and/or computed tomography (CT) thorax every 12 weeks.Following ctDNA evaluation, in the absence of progression or toxicity, subject will continue with durvalumab to complete 1 year of treatment as standard of care.
  • Durvalumab
  • Carboplatin
  • Pemetrexed
  • Paclitaxel
  • Cisplatin
Cohort 2 minimal residual disease negative (MRD )ExperimentalSubjects with undetectable ctDNA at study enrollment will receive standard of care durvalumab(10 mg/kg every 2 weeks, or equivalent, for 1 year). If subjects in Cohort 2 MRD progress prior to close of study, blood will be drawn for ctDNA testing.
  • Durvalumab

Eligibility Criteria

        Inclusion Criteria:

          1. Histologically or cytologically documented NSCLC who present with locally advanced,
             unresectable (stage III) disease (Version 8 of American Joint Committee on Cancer
             (AJCC) Staging Manual)

          2. Must have received at least 2 doses of platinum based chemotherapy concurrent with ≥
             60 Gy definitive radiation therapy to all known tumor sites, and not have known
             progression of disease.

          3. Must have received, or be scheduled to receive, 2 prior doses of durvalumab

          4. Willing to potentially receive further consolidation chemotherapy with carboplatin and
             pemetrexed or carboplatin and paclitaxel as specified by the protocol, but not be
             currently intended to receive additional consolidation chemotherapy apart from this
             protocol

          5. Aged 18 years or older

          6. Weight > 30kg

          7. Life expectancy ≥ 12 weeks

          8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

          9. Absolute neutrophil count > 1.0 x 109/L (1000/mm3)

         10. Platelets > 75 x 109/L (100,000/mm3)

         11. Hemoglobin ≥ 9.0 g/dL (5.59 mmol/L)

         12. Measured creatinine clearance > 40 mL/min, by either 24 hour urine collection or the
             Cockcroft Gault formula

             Males:

             Mass(kg) x (140-Age) / 72 x serum creatinine (mg/dL)

             Females:

             Mass(kg) x (140-Age) x 0.85 / 72 x serum creatinine (mg/dL)

         13. Serum bilirubin ≤ 1.5 x upper limit of normal (ULN). This will not apply to subjects
             with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is
             predominantly unconjugated in the absence of evidence of hemolysis or hepatic
             pathology) who will be allowed in consultation with their physician.

         14. aspartate aminotransferase (AST) (SGOT)/Alanine Aminotransferase (ALT) (SGPT) ≤ 2.5 x
             institutional upper limit of normal (ULN) unless liver metastases are present, in
             which case it must be ≤ 5 x ULN

         15. Ability to understand and the willingness to sign the written IRB approved informed
             consent document.

        Exclusion Criteria:

          1. Involvement in the planning and/or conduct of the study

          2. Previous enrollment or randomization in the present study

          3. Participation in another clinical study with an investigational product (ie, non
             standard of care) during the last 4 weeks

          4. Mixed small cell and non small cell lung cancer histology

          5. Receiving or will receive sequential chemoradiation therapy for locally advanced NSCLC

          6. History of another primary malignancy and currently undergoing active treatment (ie,
             chemotherapy, hormonal therapy, biologics)

          7. Current or prior use of immunosuppressive medication within 14 days before enrollment,
             with the exceptions of intranasal and inhaled corticosteroids or systemic
             corticosteroids at physiological doses, which are not to exceed 10 mg/day of
             prednisone, or an equivalent corticosteroid. Systemic steroid administration required
             to manage toxicities arising from radiation therapy delivered as part of the
             chemoradiation therapy for locally advanced NSCLC is allowed.

          8. Any unresolved toxicity CTCAE > Grade 2 from the prior chemoradiation therapy with the
             exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
             criteria.

               -  Subjects with Grade ≥ 2 neuropathy will be evaluated on a case by case basis
                  after consultation with the Protocol Director / Principal Investigator

               -  Subjects with irreversible toxicity that is not reasonably expected to be
                  exacerbated by treatment with durvalumab may be included (ie, hearing loss) only
                  after consultation with the Protocol Director / Principal Investigator.

          9. Any prior Grade ≥ 3 immune related adverse event (irAE) while receiving any previous
             immunotherapy agent, or any unresolved irAE > Grade 1) that may limit subject from
             continuing durvalumab during the study

         10. Recent major surgery within 4 weeks prior to entry into the study (excluding the
             placement of vascular access) that would prevent administration of study drug.

         11. Active or prior documented autoimmune or inflammatory disorders which could limit the
             subjects ability to continue durvalumab on the study (including inflammatory bowel
             disease [eg, colitis or Crohn's disease], 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 may be taken in to considerations as
             exceptions to this criterion:

               1. Vitiligo or alopecia

               2. Hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement

               3. Chronic skin condition not requiring systemic therapy

               4. Those without active disease in the last 5 years may be included, but only after
                  consultation with the study physician

               5. Celiac disease controlled by diet alone

         12. History of primary immunodeficiency

         13. History of organ transplant requiring therapeutic immunosuppression

         14. History of hypersensitivity to durvalumab, carboplatin, pemetrexed or paclitaxel

         15. Active infection including but not limited to:

               -  Tuberculosis

               -  Hepatitis B (HBV) [known positive results for HBV surface antigen (HBsAg) within
                  2 months prior to enrollment]. EXCEPTION: Subjects with a past or resolved HBV
                  infection, defined as the presence of hepatitis B core antibody (anti HBc) and
                  absence of HBsAg are eligible.

               -  Hepatitis C (HCV). EXCEPTION: Subjects positive for HCV antibody are eligible
                  only if polymerase chain reaction is negative for HCV RNA 16 .Receipt of live
                  attenuated vaccine within 30 days prior to the first dose of IP. Note: Subjects,
                  if enrolled, should not receive live vaccine while receiving the investigational
                  product (IP), and through 30 days after the last dose of IP.

        17. 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

          -  Psychiatric illness/social situations that would limit compliance with study
             requirement, substantially increase risk of incurring AEs or compromise the ability of
             the subject to give written informed consent.

             18. Female subjects who are pregnant or breast feeding; or subjects of reproductive
             potential of any gender who are not employing or who do not agree to employ an
             effective method of birth control prior to trial enrollment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Decrease in ctDNA Level Following Chemotherapy
Time Frame:12 weeks
Safety Issue:
Description:Participants in Cohort 1 MRD+ will be assessed for ctDNA levels at baseline and end of treatment, expected to be 4 cycles of 3 weeks per cycle (defined as ctDNA evaluable set or ctDES). The outcome will be assessed as the number of participants with a ≥ 3 fold decrease in ctDNA level, a number without dispersion.

Secondary Outcome Measures

Measure:Presence of Detectable ctDNA Following Chemotherapy
Time Frame:12 weeks
Safety Issue:
Description:Participants in Cohort 1 MRD+ will be assessed for ctDNA levels at baseline and end of treatment, expected to be 4 cycles of 3 weeks per cycle. The outcome will be assessed as the number of participants with or without detectable ctDNA, a number without dispersion.
Measure:Overall Survival (OS)
Time Frame:2 years
Safety Issue:
Description:Overall survival (OS) is defined as the period a participant remains alive after study registration until death due to any cause. Participants lost to follow up will be censored at last known date alive. The outcome will be reported as the number of participants in both cohorts remaining alive after 2 years, a number without dispersion.
Measure:Progression free survival (PFS)
Time Frame:2 years
Safety Issue:
Description:Progression free survival (PFS) is defined as the period a participant remains alive without disease progression after study registration. Tumor status is assessed per the Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) by computed tomography (CT), positron emission tomography (PET) CT; and/or X rays. Participants lost to follow up will be censored at last known date alive. The outcome will be reported as the number of participants in both cohorts remaining alive without progression after 2 years, a number without dispersion. Complete Response (CR) = Disappearance of all lesions Partial Response (PR) = ≥30% decrease in the sum of the lesion diameters Overall Response (OR) = CR + PR Progressive disease (PD) = 20% increase in the sum of lesion diameters, and/or the appearance of 1+ new lesion(s) Stable disease (SD) = Small changes that do not meet any of the above criteria
Measure:Durvalumab related Adverse Events (Cohort 1 MRD+ only)
Time Frame:13 months
Safety Issue:
Description:Adverse events will be collected for participants of Cohort 1 (MRD+) who initiate treatment with durvalumab through 30 days after the last dose of durvalumab. AE grade per the Common Terminology Criteria for Adverse Events (CTCAE v5) criteria and relationship to study treatment will be assessed. The outcome will be reported as the number of durvalumab related adverse events by grade that Cohort 1 MRD+ participants experienced.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Stanford University

Last Updated

October 6, 2020