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Chemoradiation Followed by Durvalumab in Poor Risk and/or Elderly Patients With Stage III NSCLC (ESR1814205)

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ClinicalTrials.gov Identifier: NCT04441138
Recruitment Status : Recruiting
First Posted : June 22, 2020
Last Update Posted : March 10, 2021
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
Gaurav Marwaha, Rush University Medical Center

Brief Summary:
Elderly (age 70 years or older) or >18 years old AND poor risk (ECOG 2) newly diagnosed stage IIIA-C (AJCC 8th edition) inoperable non-small cell lung cancer (NSCLC) patients are eligible to participate in this phase II open label study of concurrent, split course chemoradiation followed by Durvalumab (MEDI4736).

Condition or disease Intervention/treatment Phase
Stage III Non-small-cell Lung Cancer Drug: Durvalumab Phase 2

Detailed Description:

The rationale for the study is to identify another cohort of stage III NSCLC for whom adjuvant Durvalumab can be safely given, expanding its utilization and benefits. With a unique, extremely well-tolerated 4-phase split course CRT regimen preceding the administration of Durvalumab, we expect to be able to offer adjuvant Durvalumab to a significant proportion of patients on study.

Patients who have completed four cycles of chemoradiation (Radiation is 60 Gy in 30 fractions administered over 12 weeks with 1-1.5 week breaks between cycles; Chemotherapy is once every 3 weeks for up to 4 cycles) will go on to receive durvalumab (MEDI4736) monotherapy as 1500mg durvalumab (MEDI4736) via IV infusion Q4W for up to a maximum of 12 months (up to 13 doses/cycles) with the last administration on week 48 until confirmed disease progression unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.

Primary objectives are:

  1. To determine the percentage of poor risk and/or elderly unresectable stage III NSCLC patients who complete split course chemoradiation
  2. To determine the safety and tolerability of durvalumab (MEDI4736) after completion of chemoradiation in this group of patients.

Secondary Objectives are:

  1. To determine the 1-year overall survival rate
  2. To determine the 1-year progression-free survival rate
  3. To determine the 1-year loco-regional progression-free survival rate
  4. To determine rate of grade 3 and 4 toxicities with this regimen in the selected patient population

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Trial of Concurrent, Split Course Chemoradiation Followed by Durvalumab (MEDI4736) in Poor Risk and/or Elderly Patients With Newly Diagnosed Stage III Non-small Cell Lung Cancer
Actual Study Start Date : February 25, 2021
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : June 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Durvalumab

Arm Intervention/treatment
Experimental: Concurrent, Split Course Chemoradiation Followed by Durvalumab
Concurrent, Split Course Chemoradiation Followed by Durvalumab (MEDI4736) in Poor Risk and/or Elderly Patients With Newly Diagnosed Stage III Non-small Cell Lung Cancer
Drug: Durvalumab
Adjuvant Durvalumab in Poor Risk and/or Elderly Patients With Newly Diagnosed Stage III Non-small Cell Lung Cancer who have completed concurrent, split course chemoradiation without progression of disease
Other Names:
  • MEDI4736
  • imfinzi




Primary Outcome Measures :
  1. Rate of split course chemoradiation completion [ Time Frame: 3 months ]
    To determine the percentage of poor risk and/or elderly unresectable stage III NSCLC patients who complete split course chemoradiation. Objective will be assessed as a binary endpoint of yes/no completion for each patient.

  2. Number of cycles of durvalumab (MEDI4736) received for each treated patient [ Time Frame: 1 year ]
    To determine the safety and tolerability of durvalumab (MEDI4736) after completion of chemoradiation in this group of patients. Objective will be measured by (a) the number of cycles of durvalumab received for each treated patient and (b) the binary endpoint of discontinuation of durvalumab.


Secondary Outcome Measures :
  1. One-year Overall Survival (OS) [ Time Frame: 1 year ]
    To determine the 1-year overall survival rate

  2. One-year Progression-Free Survival (PFS) according to RECIST 1.1 [ Time Frame: 1 year ]
    To determine the 1-year progression-free survival rate

  3. One-Year Loco-regional Progression-free Survival (PFS) according to RECIST 1.1 [ Time Frame: 1 year ]
    To determine the 1-year loco-regional progression-free survival rate

  4. Rate of grade 3 and 4 toxicities assessed by CTCAE v 5.0 [ Time Frame: 1 year ]
    To determine rate of grade 3 and 4 toxicities with this regimen in the selected patient population



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Participants must have histologically or cytologically confirmed stage IIIA-C (AJCC 8th edition) non-small cell lung cancer, that will be treated with curative intent.
  2. Participants must have been deemed medically inoperable by multidisciplinary team/tumor board
  3. Participants must have been staged with a PET/CT within 30 days of enrollment
  4. Patients must have undergone an MRI Brain w/IV contrast, or CT brain if MRI not feasible, confirming no evidence of brain metastases, within 30 days of enrollment.
  5. Participants must be elderly (age 70 years or older and PS 0-1) or >18 years old AND poor risk (ECOG 2)
  6. Participants ideally have endobronchial ultrasound biopsy (EBUS) or mediastinoscopy to confirm nodal status, but can be deferred if PET/CT imaging characteristics are highly suggestive of nodal metastases
  7. Participants should have a life expectancy of >6 months
  8. Participants must have normal organ and marrow function: Leukocytes >3000/mcL; ANC >1500/mcL; PLT>100000/mcL; Hemoglobin ≥9.0 g/dL
  9. Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN)
  10. AST/ALT <2.5 x institutional upper limit of normal
  11. Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula

    Males:

    Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL)

    Females:

    Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL)

  12. Patients must be capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (eg, Health Insurance Portability and Accountability Act in the US, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations. If study includes Japan add (For patients aged <20 years and enrolling in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative.)
  13. Body weight >30kg
  14. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal 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 post-menopausal 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 post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).

    Women ≥50 years of age would be considered post-menopausal 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).

  15. 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.

Exclusion Criteria:

  1. History of allergic reactions attributed to compounds of similar chemical or biologic composition to carboplatin, pemetrexed (for patients with adenocarcinoma), etoposide (for patients with squamous cell carcinoma), or immunotherapy
  2. Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic CHF, unstable angina pectoris, cardiac arrhythmia, or psychiatric/social situations that would limit compliance with study requirements.
  3. Pregnant women
  4. HIV positive patients
  5. Participation in another clinical study with an investigational product during the last 6 months
  6. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
  7. Receipt of the last dose of anticancer therapy (CRT) ≤7 days prior to the first dose of study drug. If sufficient wash-out time has not occurred due to the schedule or PK properties of an agent, a longer wash-out period will be required, as agreed by AstraZeneca/MedImmune and the investigator
  8. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria

    1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
    2. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician.
  9. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
  10. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable.
  11. History of allogenic organ transplantation.
  12. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., 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 are exceptions to this criterion:

    1. Patients with vitiligo or alopecia
    2. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
    3. Any chronic skin condition that does not require systemic therapy
    4. Patients without active disease in the last 5 years may be included but only after consultation with the study physician
    5. 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. History of another primary malignancy except for

    1. Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence
    2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
    3. Adequately treated carcinoma in situ without evidence of disease
  15. History of leptomeningeal carcinomatosis
  16. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart) <<for durvalumab monotherapy.
  17. History of active primary immunodeficiency
  18. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
  19. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:

    1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
    2. Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of prednisone or its equivalent
    3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
  20. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
  21. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy.
  22. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
  23. Prior randomisation or treatment in a previous durvalumab clinical study regardless of treatment arm assignment.
  24. Patients who have received prior anti-PD-1, anti PD-L1, including durvalumab or anti CTLA-4:

    1. Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy.
    2. All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study.
    3. Must not have experienced a ≥Grade 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE: Patients with endocrine AE of ≤Grade 2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic.
    4. Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of > 10 mg prednisone or equivalent per day.
  25. Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements.

Procedures for withdrawal of incorrectly enrolled patients are presented in Section 4.3 Withdrawal of patients from study treatment and/or study


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04441138


Contacts
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Contact: Marie Baligod, RN 312-563-0789 rosemarie_baligod@rush.edu
Contact: Victoria Provido, DNP, MSN, RN 312.563.0897 Victoria_L_Provido@rush.edu

Locations
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United States, Illinois
Rush University Cancer Center Recruiting
Chicago, Illinois, United States, 60612
Contact: Gaurav Marwaha, MD       Gaurav_Marwaha@rush.edu   
Sub-Investigator: Marta Batus, MD         
Sub-Investigator: Mary Jo Fidler, MD         
Sub-Investigator: Julius Turian, PhD         
Sub-Investigator: Dian Wang, MD         
Sub-Investigator: Philip Bonomi, MD         
Sub-Investigator: Ken Tatebe         
Sponsors and Collaborators
Rush University Medical Center
AstraZeneca
Investigators
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Principal Investigator: Gaurav Marwaha, MD Rush University Cancer Center
Publications:
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Børresen-Dale AL, Boyault S, Burkhardt B, Butler AP, Caldas C, Davies HR, Desmedt C, Eils R, Eyfjörd JE, Foekens JA, Greaves M, Hosoda F, Hutter B, Ilicic T, Imbeaud S, Imielinski M, Jäger N, Jones DT, Jones D, Knappskog S, Kool M, Lakhani SR, López-Otín C, Martin S, Munshi NC, Nakamura H, Northcott PA, Pajic M, Papaemmanuil E, Paradiso A, Pearson JV, Puente XS, Raine K, Ramakrishna M, Richardson AL, Richter J, Rosenstiel P, Schlesner M, Schumacher TN, Span PN, Teague JW, Totoki Y, Tutt AN, Valdés-Mas R, van Buuren MM, van 't Veer L, Vincent-Salomon A, Waddell N, Yates LR; Australian Pancreatic Cancer Genome Initiative; ICGC Breast Cancer Consortium; ICGC MMML-Seq Consortium; ICGC PedBrain, Zucman-Rossi J, Futreal PA, McDermott U, Lichter P, Meyerson M, Grimmond SM, Siebert R, Campo E, Shibata T, Pfister SM, Campbell PJ, Stratton MR. Signatures of mutational processes in human cancer. Nature. 2013 Aug 22;500(7463):415-21. doi: 10.1038/nature12477. Epub 2013 Aug 14. Erratum in: Nature. 2013 Oct 10;502(7470):258. Imielinsk, Marcin [corrected to Imielinski, Marcin].
Lan and DeMets 1983 Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 1983;70:659 63
Brahmer et al. 2014 Brahmer JR, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA, et al. Nivolumab (anti PD 1, BMS-936558, ONO-4538) in patients (pts) with advanced non-small-cell lung cancer (NSCLC): Survival and clinical activity by subgroup analysis [ASCO abstract 8112]. J Clin Oncol 2014;32(Suppl).
o Drake et al. 2013 Drake CG, McDermott DF, Sznol M, Choueiri TK, Kluger HM, Powderly JD et al. Survival, safety, and response duration results of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in a phase I trial in patients with previously treated metastatic renal cell carcinoma (mRCC): Long-term patient follow-up [abstract 4514]. J Clin Oncol 2013;31(Suppl).
Fairman et al. 2014 Fairman D, Narwal R, Liang M, Robbins PB, Schneider A, Chavez C, et al. Pharmacokinetics of durvalumab, a fully human anti-PDL1 monoclonal antibody, in patients with advanced solid tumours. Journal of Clinical Oncology, 2014 ASCO Annual Meeting Abstracts;32(5s): (suppl; abstr 2602).
Herbst et al. 2013 Herbst RS, Gordon MS, Fine GD, Sosman JA, Soria JC, Hamid O, et al. A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumours [abstract 3000]. J Clin Oncol 2013;31(Suppl 15).
Hodi et al. 2014 Hodi FS, Sznol M, Kluger HM, McDermott DF, Carvajal RD, Lawrence DP et al. Long-term survival of ipilimumab-naive patients (pts) with advanced melanoma (MEL) treated with nivolumab (anti-PD-1, BMS-936558, ONO-4538) in a Phase I trial [ASCO abstract 9002]. J Clin Oncol 2014; 32(Suppl).
Rizvi et al. 2015 Rizvi N, Brahmer J, Ou S-H, Segal NH, Khleif SN, Hwu WJ. Safety and clinical activity of MEDI4736, an anti-programmed cell death-ligand-1 (PD-L1) antibody, in patients with nonsmall cell lung cancer (NSCLC). J Clin Oncol 2015;33:Abstract 8032.
Schadendorf et al. 2013 Schadendorf D, Hodi FS, Robert C et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable melanoma [abstract 24]. Presented at European Cancer Congress 2013 (ECCO-ESMO-ESTRO); 27 September to 01 October 2013; Amsterdam, The Netherlands.
Segal et al. 2015 Segal NH, Ou S-HI, Balmanoukian AS, Fury MG, Massarelli E, Brahmer JR, et al. Safety and efficacy of MEDI4736, an anti-PD-L1 antibody, in patients from a squamous cell carcinoma of the head and neck (SCCHN) expansion cohort. J Clin Oncol 2015;33:Abstract 3011.

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Responsible Party: Gaurav Marwaha, Principal Investigator, Rush University Medical Center
ClinicalTrials.gov Identifier: NCT04441138    
Other Study ID Numbers: ESR 18-14205
First Posted: June 22, 2020    Key Record Dates
Last Update Posted: March 10, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Gaurav Marwaha, Rush University Medical Center:
Stage III NSCLC
Durvalumab
Elderly
Poor-risk
chemoradiation
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Durvalumab
Antineoplastic Agents, Immunological
Antineoplastic Agents