Durvalumab and Tremelimumab in Treating Patients With Recurrent Stage IV Lung Cancer

• ClinicalTrials.gov Identifier: NCT03373760
• Recruitment Status: Completed
• First Posted: December 14, 2017
• Results First Posted: January 21, 2022
• Last Update Posted: June 9, 2023
• Sponsor: SWOG Cancer Research Network
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): SWOG Cancer Research Network

Tracking Information

• First Submitted Date: December 11, 2017
• First Posted Date: December 14, 2017
• Results First Submitted Date: November 8, 2021
• Results First Posted Date: January 21, 2022
• Last Update Posted Date: June 9, 2023
• Actual Study Start Date: November 30, 2017
• Actual Primary Completion Date: May 18, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 7, 2023)

Objective Response Rate [ Time Frame: From date of registration to progression or treatment discontinuation, up to 2 years and 5.5 months. ]

Percentage of participants with confirmed or unconfirmed, complete or partial response to treatment with MEDI4736 (durvalumab) plus tremelimumab per Response Evaluation Criteria in Solid Tumors Criteria (RECIST 1.1). Complete Response (CR): Complete disappearance of all target and non-target lesions. No new lesions. No disease related symptoms. Any lymph nodes (whether target or non-target) must have reduction in short axis to < 1.0 cm. All disease must be assessed using the same technique as baseline. Partial Response (PR): Applies only to patients with at least one measurable lesion. Greater than or equal to 30% decrease under baseline of the sum of appropriate diameters of all target measurable lesions. No unequivocal progression of non-measurable disease. No new lesions. All target measurable lesions must be assessed using the same techniques as baseline.

Original Primary Outcome Measures (submitted: December 11, 2017)

Objective response rate assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 [ Time Frame: Up to 3 years ]

Estimated within 13% with 95% confidence.

Current Secondary Outcome Measures (submitted: June 7, 2023)

• Duration of Response (DoR) Among Patients Who Achieve a Complete Response (CR) or Partial Response (PR) (Confirmed and Unconfirmed) by RECIST 1.1. [ Time Frame: From date of registration to maximum of 2 years and 5.5 months or death. ]
  Time from date of first documentation of response (CR or PR) to date of first documentation of progression assessed by local review or symptomatic deterioration, or death from any cause among patients who achieve a response. Patients last known to be alive without report of progression are censored at date of last disease assessment. For patients with a missing scan (or consecutive missing scans) whose subsequent scan determines progression, the expected date of the first missing scan will be used as the date of progression. Progression is defined as one or more of the following: 20% increase in the sum of appropriate diameters of target measurable lesions over smallest sum observed and an absolute increase of at least 0.5 cm; Unequivocal progression of non-measurable disease in the opinion of the treating physician (explanation must be provided); Appearance of any new lesion/site; Death due to disease without prior documentation of progression and without symptomatic deterioration
• Duration of Response (DoR) Per Immune-related Response Criteria Among Patients Who Achieve a Complete Response (CR) or Partial Response (PR) (Confirmed and Unconfirmed) by RECIST 1.1 [ Time Frame: From date of registration to maximum of 2 years and 5.5 months or death ]
  Time from date of first documentation of response (CR or PR) to date of first documentation of irRC-progression assessed by local review or symptomatic deterioration, or death due to any cause. Patients last known to be alive without report of irRC-progression are censored at date of last disease assessment. For patients with a missing scan (or consecutive missing scans) whose subsequent scan(s) determine irRC-progression, the date of irRCprogression will be the expected date of the first missing scan (as defined by the disease assessment schedule) or the date of the first scan documenting potential irRC-progression, whichever is earliest.
• Overall Survival (OS) Among Patients Treated With MEDI4736 (Durvalumab) Plus Tremelimumab [ Time Frame: Date of registration to maximum of 2 years and 5.5 months or death. ]
  Time from date of sub-study registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact.
• Investigator-assessed Progression-free Survival (IA-PFS) Among Patients Treated With MEDI4736 (Durvalumab) Plus Tremelimumab. [ Time Frame: From date of registration to maximum 2 years and 5.5 months or death. ]
  Time from date of sub-study registration to date of first documentation of progression assessed by local review or symptomatic deterioration, or death due to any cause. Patients last known to be alive without report of progression are censored at date of last disease assessment. For patients with a missing scan (or consecutive missing scans) whose subsequent scan determines progression, the expected date of the first missing scan (as defined by the disease assessment schedule) was used as the date of progression. Progression is defined as one or more of the following: 20% increase in the sum of appropriate diameters of target measurable lesions over smallest sum observed and an absolute increase of at least 0.5 cm; Unequivocal progression of non-measurable disease in the opinion of the treating physician (an explanation must be provided); Appearance of any new lesion/site; Death due to disease without prior documentation of progression and without symptomatic deterioration.
• Investigator-assessed Progression-free Survival (IA-PFS) Assessed by Immune-related Response Criteria (irRC-IA-PFS) Among Patients Treated With MEDI4736 (Durvalumab) Plus Tremelimumab [ Time Frame: Date of registration to maximum of 2 years and 5.5 months or death ]
  Time from date of sub-study registration to date of first documentation of progression assessed by local review or symptomatic deterioration, or death due to any cause. Patients last known to be alive without report of progression are censored at date of last disease assessment. For patients with a missing scan (or consecutive missing scans) whose subsequent scan determines progression, the expected date of the first missing scan (as defined by the disease assessment schedule) will be used as the date of progression. irRC-progression is defined by progression per RECIST 1.1 except that progression determined by appearance of new lesions or by a 20% increase in the sum of diameters must be confirmed by a second consecutive determination of progression at least 28 days from the date of initial documentation of progression.
• Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs [ Time Frame: Duration of treatment and follow up until death or 2 years and 5.5 months post registration ]
  Only adverse events that are possibly, probably or definitely related to study drug are reported. CTCAE Version 4.0 was used for routine toxicity reporting and CTCAE Version 5.0 was used for reporting serious adverse events (SAEs).

Original Secondary Outcome Measures (submitted: December 11, 2017)

• Duration of response (DOR) [ Time Frame: Up to 3 years ]
  Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to calculate confidence intervals for median DOR.
• Immune-Related Response Criteria investigator-assessed progression-free survival (irRC-IA-PFS) assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 [ Time Frame: From date of registration to date of first documentation of irRC progression or death due to any cause, assessed up to 3 years ]
  Will be estimated using the method of Kaplan-Meier.
• Incidence of adverse events assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 3 years ]
  Toxicity rates can be estimated within 13% with 95% confidence. Any toxicity with at least 5% prevalence has at least a 95% chance of being observed.
• Investigator-assessed progression-free survival (IA-PFS) [ Time Frame: 6 months after completion of accrual ]
  Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to calculate confidence intervals for median IA-PFS.
• Overall survival (OS) [ Time Frame: 6 months after completion of accrual ]
  Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to calculate confidence intervals for median OS.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Durvalumab and Tremelimumab in Treating Patients With Recurrent Stage IV Lung Cancer
• Official Title: A Phase II Study of MEDI4736 (Durvalumab) Plus Tremelimumab as Therapy for Patients With Previously Treated Anti-PD-1/PD-L1 Resistant Stage IV Squamous Cell Lung Cancer (Lung-Map Non-Match Sub-Study)
• Brief Summary: This phase II trial studies how well durvalumab and tremelimumab works in treating patients with stage IV lung cancer that has come back after previous treatment. Monoclonal antibodies, such as durvalumab and tremelimumab, may interfere with the ability of tumor cells to grow and spread.

Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate the objective response rate (confirmed and unconfirmed, complete and partial) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 among patients treated with durvalumab (MEDI4736) plus tremelimumab.

SECONDARY OBJECTIVES:

I. To estimate the duration of response (DoR) among patients who achieve a complete response (CR) or partial response (PR) (confirmed and unconfirmed) by RECIST 1.1.

II. To estimate the duration of response (DoR) per immune-related response criteria among patients who achieve a complete response (CR) or partial response (PR) (confirmed and unconfirmed) by RECIST 1.1.

III. To evaluate overall survival (OS) among patients treated with durvalumab (MEDI4736) plus tremelimumab.

IV. To evaluate investigator-assessed progression-free survival (IA-PFS) among patients treated with durvalumab (MEDI4736) plus tremelimumab.

V. To evaluate IA-PFS assessed by immune-related response criteria (irRC-IA-PFS) among patients treated with durvalumab (MEDI4736) plus tremelimumab.

VI. To evaluate the frequency and severity of toxicities associated with durvalumab (MEDI4736) plus tremelimumab.

TERTIARY OBJECTIVES:

I. To explore the association of potential predictive markers identified in S1400A, with response and progression-free survival (PFS).

II. To explore the association of PD-L1 expression status with response and PFS.

III. To contribute to an ongoing serum and tumor bank in S1400.

OUTLINE:

Patients receive tremelimumab intravenously (IV) over 60 minutes on day 1 for courses 1-4 and durvalumab IV over 60 minutes on day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 2 years, and then at the end of year 3.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Recurrent Squamous Cell Lung Carcinoma
• Stage IV Squamous Cell Lung Carcinoma AJCC v7

Intervention

• Biological: Durvalumab
  Given IV
  Other Names:

  • Imfinzi
  • Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer
  • MEDI-4736
  • MEDI4736
• Other: Laboratory Biomarker Analysis
  Correlative studies
• Biological: Tremelimumab
  Given IV
  Other Names:

  • Anti-CTLA4 Human Monoclonal Antibody CP-675,206
  • CP-675
  • CP-675,206
  • CP-675206
  • ticilimumab

Study Arms

Experimental: Treatment (tremelimumab, durvalumab)

Patients receive tremelimumab IV over 60 minutes on day 1 for courses 1-4 and durvalumab IV over 60 minutes on day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Interventions:

• Biological: Durvalumab
• Other: Laboratory Biomarker Analysis
• Biological: Tremelimumab

• Publications *: Leighl NB, Redman MW, Rizvi N, Hirsch FR, Mack PC, Schwartz LH, Wade JL, Irvin WJ, Reddy SC, Crawford J, Bradley JD, Stinchcombe TE, Ramalingam SS, Miao J, Minichiello K, Herbst RS, Papadimitrakopoulou VA, Kelly K, Gandara DR. Phase II study of durvalumab plus tremelimumab as therapy for patients with previously treated anti-PD-1/PD-L1 resistant stage IV squamous cell lung cancer (Lung-MAP substudy S1400F, NCT03373760). J Immunother Cancer. 2021 Aug;9(8):e002973. doi: 10.1136/jitc-2021-002973.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 8, 2021): 67
• Original Estimated Enrollment (submitted: December 11, 2017): 132
• Actual Study Completion Date: March 29, 2022
• Actual Primary Completion Date: May 18, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patients must have been assigned to S1400F
• Patients must have progressed during or after prior platinum-based chemotherapy; patients whose only prior platinum-based chemotherapy regimen was for stage I-III disease (i.e. patient has not received any platinum-based chemotherapy for stage IV or recurrent disease), disease progression on platinum-based chemotherapy must have occurred within one year from the last date that patient received that therapy; patients must have experienced disease progression during or after prior anti-PD-1 or anti-PD-L1 antibody monotherapy as their most recent line of treatment; prior PD-1/PD-L1 combination therapy is not permitted
• Prior exposure to CTLA-4 inhibitors (ipilimumab and tremelimumab) is not permitted; prior exposure to the following is allowed: attenuated vaccines, anti-EGFR agents, and granulocyte-macrophage colony-stimulating factor (GM-CSF)
• Patients must not have received nitrosoureas or mitomycin-C within 42 days prior to sub-study registration
• Patients must not have any prior documented autoimmune or inflammatory disease (including inflammatory bowel disease, diverticulitis with the exception of diverticulosis, celiac disease, irritable bowel disease; Wegner syndrome; Hashimoto syndrome) within 3 years prior to sub-study registration; patients with vitiligo, immune-mediated alopecia, Grave?s disease, or psoriasis requiring systemic treatment within the past 2 years are not eligible; patients with hypothyroidism (e.g. post Hashimoto syndrome) who are stable on hormone replacement therapy are eligible
• Patients must not have any history of primary immunodeficiency
• Patients must not have received any immunosuppressive medication within 28 days prior to sub-study registration and must not be planning to receive these medications while on protocol therapy; systemic corticosteroids must be stopped at least 24 hours prior to sub-study registration; however, intranasal and inhaled corticosteroids are allowed at any time before and during protocol therapy
• Patients must not have experienced a grade 3 or worse immune-related adverse event (irAE) (except asymptomatic nonbullous/nonexfoliative rash) or any unresolved irAE grade 2, nor have experienced a toxicity that led to permanent discontinuation of prior anti-PD-1/PD-L1 immunotherapy
• Patients must not have any history of organ transplant that requires use of immunosuppressives
• Patients must not have any known allergy or reaction to any component of the durvalumab (MEDI4736) and/or tremelimumab formulation
• Patients must not have clinical signs or symptoms of active tuberculosis infection
• Patients must not have received a live attenuated vaccination within 28 days prior to sub-study registration
• Patients must not have known human immunodeficiency virus (HIV), or a known positive test for hepatitis B virus surface antigen (HBV sAg), or hepatitis C virus ribonucleic acid (HCV antibody) indicating current acute or chronic infection; patients with a positive hepatitis C antibody with a negative viral load are allowed
• Patients must have a thyroid-stimulating hormone (TSH) with reflex free T3/free T4 (if TSH is out of normal range) and electrocardiogram (EKG) obtained within 7 days prior to sub-study registration
• Patients must also be offered participation in banking and in the correlative studies for collection and future use of specimens

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03373760
• Other Study ID Numbers: S1400F; NCI-2016-01597 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); S1400F; S1400F ( Other Identifier: SWOG ); S1400F ( Other Identifier: CTEP ); U10CA180888 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: SWOG Cancer Research Network
• Original Responsible Party: Same as current
• Current Study Sponsor: SWOG Cancer Research Network
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Vassiliki Papadimitrakopoulou; SWOG Cancer Research Network

• PRS Account: SWOG Cancer Research Network
• Verification Date: June 2023