## Protocol Section
### Identification Module
**NCT ID:** NCT03262779

**Brief Title:** Ipilimumab and Nivolumab in Patients With Anti-PD-1-axis Therapy-resistant Advanced Non-small Cell Lung Cancer.

**Official Title:** A Phase II Study of Combination Immunotherapy With Ipilimumab and Nivolumab in Patients With Advanced Non-small Cell Lung Cancer Resistant to Anti-PD-1-axis Therapy

#### Organization Study ID Info
**ID:** 2000020343
#### Organization
**Class:** OTHER
**Full Name:** Yale University
### Status Module
#### Completion Date
**Date:** 2022-01-14

**Type:** ACTUAL

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2022-09-23

**Type:** ACTUAL

**Last Update Submit Date:** 2022-09-21

**Overall Status:** COMPLETED

#### Primary Completion Date
**Date:** 2022-01-14

**Type:** ACTUAL

#### Start Date
**Date:** 2017-07-20

**Type:** ACTUAL

**Status Verified Date:** 2022-09

#### Study First Post Date
**Date:** 2017-08-25
**Type:** ACTUAL
**Study First Submit Date:** 2017-08-23
**Study First Submit QC Date:** 2017-08-23
### Sponsor Collaborators Module

#### Collaborators

**Class:** INDUSTRY

**Name:** Bristol-Myers Squibb

#### Lead Sponsor

**Class:** OTHER

**Name:** Yale University

#### Responsible Party

**Investigator Affiliation:** Yale University

**Investigator Full Name:** Scott Gettinger, MD

**Investigator Title:** Assistant Professor of Medicine

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** True

**Oversight Has DMC:** True

### Description Module

**Brief Summary:** The investigators propose a trial to evaluate if the addition of ipilimumab to nivolumab after primary or acquired resistance to anti- programmed death 1 (PD-1) axis therapy can lead to objective radiographic tumor regression.

**Detailed Description:** Approximately 20 percent of unselected patients with advanced non-small cell lung cancer (NSCLC) and progression during or after standard first line chemotherapy will experience tumor response to nivolumab. Treatment options for patients who are not responsive to programmed death 1 (PD-1) axis inhibitor therapy are limited, and the mechanisms of primary resistance are poorly understood.

The combination of nivolumab and ipilimumab is currently FDA approved for the treatment of advanced melanoma based on superiority to either agent alone5. The results of a phase I study evaluating combination therapy with nivolumab and ipilimumab in patients with advanced NSCLC (NCT01454102) were presented at the annual American Society of Clinical Oncology (ASCO) meeting in 20166. Dosing of nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks yielded an objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 of 39%, with one-year survival rate of 69% and grade 3-4 treatment-related adverse event rate of 33%. These results prompted an ongoing phase III study comparing this regimen to standard first line chemotherapy, nivolumab monotherapy or combination therapy with chemotherapy and nivolumab for patients with advanced NSCLC (NCT02477826).

The investigators propose a trial to evaluate if the addition of ipilimumab to nivolumab after primary resistance to anti-PD-1 axis therapy can lead to objective radiographic tumor regression. It is hypothesized that ipilimumab will enable more effective immune priming in some patients, resulting in the trafficking of tumor-specific cytotoxic T cells to the tumor, as well as depletion of tumor-permissive T regulatory cells. With concurrent nivolumab, PD-1 inhibition in the tumor will enable effective anti-tumor attack by tumor-specific T cells. Serial tumor biopsies and blood collections will allow interrogation of changes in the tumor microenvironment (and periphery) that support this hypothesis.

The investigators will primarily enroll patients who have experienced progression of NSCLC after anti-PD-1- axis therapy without initial response to such therapy ('primary resistance'). A smaller cohort of patients with acquired resistance to anti-PD-1 axis therapy (i.e. progression after initial response) will additionally be accrued.

The study record was updated to add individual arms for those with primary resistance and acquired resistance. The intent of the study is not to compare these treatment arms.

### Conditions Module

**Conditions:**

- Carcinoma, Non-Small-Cell Lung

### Design Module

#### Design Info

**Allocation:** NON_RANDOMIZED

**Intervention Model:** SINGLE_GROUP

**Intervention Model Description:** This a phase II study employing a Simon two-stage design. If there is at least one response or prolonged stability (\> 24 weeks) using immune related Response Criteria (irRC) appreciated in the first 10 patients who initiate trial therapy, a total of 40 patients will be enrolled. An additional 10 patients with acquired resistance to anti-PD-1 axis therapy will be enrolled in an exploratory cohort receiving the same therapy.

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 20

**Type:** ACTUAL

**Phases:**

- PHASE2

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Combination therapy with nivolumab 3 mg/kg administered intravenously (IV) every 2 weeks, and ipilimumab 1 mg/kg administered IV every 6 weeks in patients with primary resistance.

**Intervention Names:**

- Biological: combination nivolumab and ipilimumab

**Label:** combination nivolumab and ipilimumab - primary

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** Combination therapy with nivolumab 3 mg/kg administered intravenously (IV) every 2 weeks, and ipilimumab 1 mg/kg administered IV every 6 weeks in patients with acquired resistance.

**Intervention Names:**

- Biological: combination nivolumab and ipilimumab

**Label:** combination nivolumab and ipilimumab - acquired

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- combination nivolumab and ipilimumab - acquired

- combination nivolumab and ipilimumab - primary

**Description:** Combination therapy with nivolumab 3 mg/kg administered intravenously (IV) every 2 weeks, with ipilimumab 1 mg/kg administered IV every 6 weeks.

**Name:** combination nivolumab and ipilimumab

**Type:** BIOLOGICAL

### Outcomes Module

#### Primary Outcomes

**Description:** Objective response is defined as a complete or partial response, as determined by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 confirmed by repeat assessment ≥4 weeks after initial documentation.

**Measure:** Objective response rate using RECIST v1.1 to nivolumab and ipilimumab when administered in combination to patients with pre-treated advanced NSCLC who have experienced primary resistance to anti-PD-1 axis therapy as their last line of systemic therapy.

**Time Frame:** Tumor response assessment will occur every 9 weeks after initiating trial therapy for the first 24 weeks, and thereafter every 12 weeks until disease progression or up to 4 years.

#### Secondary Outcomes

**Description:** Progression free survival is defined as the time from the first day of nivolumab treatment until progression of disease using RECIST v1.1 and immune related Response Criteria (irRC)

**Measure:** Progression-free survival with nivolumab and ipilimumab when administered in combination to patients with pre- treated advanced NSCLC who have experienced primary resistance to anti-PD-1 axis therapy as their last line of systemic therapy

**Time Frame:** Until disease progression, unacceptable toxicity, or study termination, up to four years.

**Description:** Overall survival is defined as the time from the first day of treatment until death from any cause. If a patient has not experienced death, OS will be censored at the day of last follow-up.

**Measure:** Overall survival (OS) with nivolumab and ipilimumab when administered in combination to patients with pre- treated advanced NSCLC who have experienced PRIMARY resistance to anti-PD-1 axis therapy as their last line of systemic therapy.

**Time Frame:** Until death or day of last follow-up, up to four years from enrollment.

**Description:** Objective response is defined as a complete or partial response, as determined by investigator assessment using irRC and confirmed by repeat assessment ≥4 weeks after initial documentation.

**Measure:** Objective response rate using irRC to nivolumab and ipilimumab when administered in combination to patients with pre-treated advanced NSCLC who have experienced primary resistance to anti-PD-1 axis therapy as their last line of systemic therapy.

**Time Frame:** Tumor response assessment will occur every 9 weeks after initiating trial therapy for the first 24 weeks, and thereafter every 12 weeks, up to four years.

**Description:** Objective response is defined as a complete or partial response, as determined by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and immune-related Response Criteria and confirmed by repeat assessment ≥4 weeks after initial documentation.

**Measure:** Objective response rate in in advanced non-small cell lung cancer (NSCLC) with ACQUIRED resistance to anti-programmed death (PD)-1 axis therapy as their last line of systemic therapy.

**Time Frame:** Tumor response assessment will occur every 9 weeks after initiating trial therapy for the first 24 weeks, and thereafter every 12 weeks, up to four years.

**Description:** Progression free survival is defined as the time from the first day of nivolumab treatment until progression of disease using RECIST v1.1 and immune related Response Criteria

**Measure:** Progression free survival by RECIST v1.1 with nivolumab and ipilimumab in patients with pre-treated advanced NSCLC who have experienced acquired resistance to anti-PD-1 axis therapy as their last line of systemic therapy.

**Time Frame:** Until disease progression, unacceptable toxicity, or study termination, up to four years from enrollment.

**Description:** Overall survival is defined as the time from the first day of treatment until death from any cause. If a patient has not experienced death, OS will be censored at the day of last follow-up.

**Measure:** Overall survival with nivolumab and ipilimumab in patients with pre-treated advanced NSCLC who have experienced ACQUIRED resistance to anti-PD-1 axis therapy as their last line of systemic therapy.

**Time Frame:** Until death or day of last follow-up (up to four years from study enrollment).

**Description:** Determined based on adverse events which will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0.

**Measure:** Safety of nivolumab and ipilimumab when administered in combination in patients with pre-treated advanced NSCLC who have experienced PRIMARY or ACQUIRED resistance to anti-PD-1 axis therapy as their last line of systemic therapy.

**Time Frame:** From date of first treatment until 100 days from discontinuation of treatment.

**Measure:** Feasibility of sequential biopsies (performed or not performed) in patients with pre-treated advanced NSCLC who have experienced PRIMARY or ACQUIRED resistance to anti-PD-1 axis therapy as their last line of systemic therapy,

**Time Frame:** Tumor biopsies will be performed just prior to initiating trial therapy, and 9 to 10 weeks after receiving first dose of trial therapy.

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria

A. Signed Informed Consent B. Ability to comply with the protocol C. Age ≥18 years D. Histologically or cytologically documented, locally advanced or metastatic (i.e., Stage IIIB not eligible for definitive chemoradiotherapy, Stage IV, or recurrent) NSCLC (per the American Joint Committee /AJCC staging system) E. ECOG performance status of 0 to 2 F. Measurable disease, as defined by RECIST v1.1. Previously irradiated lesions can be counted as target lesions if clearly progressing after radiation.

G. Chemotherapy-naive and treated patients will be eligible, with no limit on number of prior therapies. Patients with NSCLC known to harbor an ALK rearrangement, or EGFR mutation known to be sensitive to FDA-approved tyrosine kinase inhibitors (TKI), are only eligible after experiencing disease progression (during or after treatment) or intolerance to an FDA approved EGFR TKI or ALK TKI, respectively.

1. Patients with TKI-treated EGFR mutant NSCLC harboring the secondary EGFR T790M tumor must have received prior osimertinib
2. Patients with crizotinib-treated ALK rearranged NSCLC must have received a next generation ALK inhibitor (e.g. ceritinib, alectinib or brigatinib) H. Prior palliative radiotherapy must have been completed at least 2 weeks before the first dose of study drug.

I. Anti- PD-1 Axis therapy (anti-PD-1 or anti-PD-L1, e.g. nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab) must be the most recent systemic anti-tumor treatment received in all patients, with documented progressive disease. Last administration of anti-PD-1 axis therapy must have been at least 3 weeks before the first dose of study drug.

a. Patients to be enrolled to the primary cohort (primary resistance) must have had progressive disease or stable disease less than 24 weeks as the best clinical response to anti-PD-1-axis monotherapy b. Patients to be enrolled to the exploratory cohort (acquired resistance) must have had stable disease for at least 24 weeks, partial response, or complete response as the best clinical response to anti-PD-1-axis monotherapy, with subsequent progression of disease J. At least one tumor amenable to incisional, excisional, core or forceps (transbronchial) biopsy. Patients must be willing to undergo tumor biopsies before starting trial therapy, and 9 to 10 weeks after initiation of therapy.

a. If the initial biopsy will be excisional, the excised tumor cannot be counted as a target lesion and there must be another lesion amenable to incisional, excisional, core or forceps biopsy. In this scenario, the second biopsy can only be excisional if the lesion to be excised is not a target lesion. b. Cytology tumor specimens (e.g. from fine-needle biopsies, or drainage of pleural/ pericardial or ascites fluid) are not acceptable. Biopsies of bone lesions that do not have a soft tissue component are also not acceptable (i.e. decalcified tumor samples are not acceptable).

K. For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception (i.e., one that results in a low failure rate \[\<1% per year\] when used consistently and correctly) and to continue its use for 6 months after the last dose of trial therapy. Highly effective contraception is one with a failure rate of \<0.1%. Birth control pills on their own do not achieve that rate.

1. Women of childbearing potential must have a negative pregnancy test (serum or urine) within 72 hours of the start of study drug administration
2. Women who have recently given birth must no longer be breastfeeding

L. Adequate hematologic and end-organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment:

- Neutrophils ≥1500 cells/μL (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1)

* Platelets ≥75,000/μL (transfusion to achieve this level is not permitted within 2 weeks of the first study drug administration)
* Hemoglobin ≥9.0 g/dL
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x institutional upper limit of normal (ULN) with the following exceptions: Patients with documented liver metastases: AST and/or ALT≤5 x ULN
* Serum bilirubin ≤1.5 x ULN (Patients with known Gilbert disease who have serum bilirubin level ≤3 x ULN may be enrolled)
* Serum creatinine ≤1.5 x ULN or creatinine clearance ≥50 mL/min

Exclusion Criteria

A. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects who require intermittent use of inhaled steroids or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement, or psoriasis not requiring systemic therapy (within the past 3 years) will not be excluded from the study. B. Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity C. Subjects must not have a history of life-threatening toxicity related to prior anti-PD-1 axis therapy a. Subjects with history of anti-PD-1 axis therapy toxicities that are unlikely to recur with standard countermeasures (e.g., hormone replacement after adrenal crisis) are eligible.

D. Prior treatment with anti-CTLA-4 therapeutic antibodies

E. Symptomatic or untreated CNS metastases. Patients with a history of treated asymptomatic CNS metastases are eligible, provided they meet all of the following criteria:

1. No evidence of interim progression between the completion of CNS-directed therapy and the start of trial therapy.
2. No ongoing requirement for dexamethasone as therapy for CNS disease; anticonvulsants at a stable dose are allowed.
3. Completed stereotactic radiosurgery at least 1 week prior to Cycle 1, Day 1 or wholebrain radiation at least 2 weeks prior to Cycle 1, Day 1 F. History of leptomeningeal carcinomatosis G. Prior palliative radiotherapy outside the CNS within 2 weeks of the first dose of study drug.

H. Treatment with systemic immunosuppressive medications (including but not limited to, dexamethasone at doses \> 2 mg daily (or equivalent dose of other corticosteroids), cyclophosphamide, tacrolimus, sirolimus, azathioprine, methotrexate, thalidomide, and antitumor necrosis factor \[anti-TNF\] agents) within 2 weeks prior to initiating trial therapy (Inhaled or topically applied steroids, and acute and chronic standard-dose NSAIDs are permitted. Replacement steroids are also permitted).

I. Subjects must not have received vaccines containing live virus for prevention of infectious diseases within 12 weeks prior to the first dose of study drug.

a. The use of inactivated seasonal influenza vaccines (eg, Fluzone®) will be permitted on study without restriction.

J. Any approved systemic anti-cancer therapy, within 3 weeks prior to initiation of study treatment; the following exception is allowed:

* TKIs approved for treatment of NSCLC discontinued \> 7 days prior to Cycle 1, Day 1. The baseline scan must be obtained after discontinuation of prior TKIs.

K. Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days prior to enrollment; the following exceptions are allowed:

* Unapproved/experimental TKIs discontinued 14 days prior to Cycle 1, Day 1 L. Known infection with HIV, HBV or HCV. Patients with prior exposure to hepatitis, but no evidence of active or chronic infection, may be eligible.
* Subjects with positive hepatitis C antibody and negative quantitative hepatitis C by polymerase chain reaction are eligible.

M. Active systemic infection requiring systemic antibiotic treatment within 72 hours prior to first dose of study treatment N. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements O. Major surgery or traumatic injury within 4 weeks of starting study drug P. Women who are pregnant or lactating. Q. Any underlying medical condition that in the Principal Investigator's opinion will make the administration of study drug hazardous to the patient or would obscure the interpretation of adverse events.

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Locations

**Location 1:**

**City:** New Haven

**Country:** United States

**Facility:** Yale Cancer Center

**State:** Connecticut

**Zip:** 06510

#### Overall Officials

**Official 1:**

**Affiliation:** Yale University

**Name:** Scott Gettinger, M.D.

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**IPD Sharing:** NO

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000002283

- Term: Carcinoma, Bronchogenic

- ID: D000001984

- Term: Bronchial Neoplasms

- ID: D000008175

- Term: Lung Neoplasms

- ID: D000012142

- Term: Respiratory Tract Neoplasms

- ID: D000013899

- Term: Thoracic Neoplasms

- ID: D000009371

- Term: Neoplasms by Site

- ID: D000009369

- Term: Neoplasms

- ID: D000008171

- Term: Lung Diseases

- ID: D000012140

- Term: Respiratory Tract Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC04

- Name: Neoplasms

- Abbrev: All

- Name: All Conditions

- Abbrev: BC08

- Name: Respiratory Tract (Lung and Bronchial) Diseases

### Condition Browse Module - Browse Leaves

- ID: M5534

- Name: Carcinoma

- Relevance: LOW

- As Found: Unknown

- ID: M11172

- Name: Lung Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M5546

- Name: Carcinoma, Non-Small-Cell Lung

- Relevance: HIGH

- As Found: Carcinoma, Non-Small-Cell Lung

- ID: M5540

- Name: Carcinoma, Bronchogenic

- Relevance: LOW

- As Found: Unknown

- ID: M5260

- Name: Bronchial Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M14979

- Name: Respiratory Tract Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M16658

- Name: Thoracic Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M11168

- Name: Lung Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M14977

- Name: Respiratory Tract Diseases

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000002289

- Term: Carcinoma, Non-Small-Cell Lung

### Intervention Browse Module - Ancestors

- ID: D000074322

- Term: Antineoplastic Agents, Immunological

- ID: D000000970

- Term: Antineoplastic Agents

- ID: D000082082

- Term: Immune Checkpoint Inhibitors

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

### Intervention Browse Module - Browse Branches

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: ANeo

- Name: Antineoplastic Agents

### Intervention Browse Module - Browse Leaves

- ID: M2853

- Name: Immunomodulating Agents

- Relevance: LOW

- As Found: Unknown

- ID: M1854

- Name: Nivolumab

- Relevance: HIGH

- As Found: Prospective

- ID: M1348

- Name: Ipilimumab

- Relevance: HIGH

- As Found: While

- ID: M1346

- Name: Antineoplastic Agents, Immunological

- Relevance: LOW

- As Found: Unknown

- ID: M2342

- Name: Immune Checkpoint Inhibitors

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000077594

- Term: Nivolumab

- ID: D000074324

- Term: Ipilimumab

### Misc Info Module

#### Submission Tracking

- Estimated Results First Submit Date: 2023-04-14

##### Submission Infos

- MCP Release N: 7

- Release Date: 2023-04-14

- Reset Date: 2023-05-09

- Unrelease Date: Unknown

- Unrelease Date Unknown: Unknown

- Version Holder: 2024-05-24
