Study of Combined Ionizing Radiation and Ipilimumab in Metastatic Non-small Cell Lung Cancer (NSCLC)

• Sponsor: NYU Langone Health (Other)
• Overall Status: Completed
• CT.gov ID: NCT02221739
• Collaborator: Bristol-Myers Squibb (Industry)
• Enrollment: 39
• Locations: 2
• Arm: 1
• Actual Duration (Months): 15.9
• Patients Per Site: 19.5
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

The purpose of this study is to investigate how effective and how safe the combination of radiation therapy and an investigational medication targeting the immune system known as Ipilimumab in the treatment of metastatic non-small cell lung cancer (NSCLC).

The investigators would like to see if this combination of radiation and Ipilimumab can stimulate the body's immune system to stop the growth of tumors that are outside the field of radiation. The investigators would like see if using this combination of radiation therapy with Ipilimumab could help the body reject the patient's own tumor or at least help their immune system to maintain the disease stable and/or slow its growth.

Radiation therapy (RT) is currently a standard procedure for treatment of NSCLC. Ipilimumab is considered an investigational medication because it is not approved by the Food and Drug Administration (FDA) for the treatment of NSCLC. Ipilimumab has been approved by the FDA for the treatment of metastatic melanoma.

Condition or Disease	Intervention/Treatment	Phase
Non-small Cell Lung Cancer (NSCLC)	Drug: Ipilimumab; Radiation: Radiotherapy (IMRT or 3-D CRT)	Phase 1/Phase 2

Detailed Description

Research Hypothesis:

1. Through a combination of local RT and ipilimumab an anti-tumor immune response is elicited at the irradiated site, as an in vivo, individualized immunization that is systemically effective, as reflected by objective responses outside the RT field (abscopal effect).

2. The immune response can be prospectively monitored among the treated patients.

Objective 1: Evaluate the safety and therapeutic efficacy of anti-cytotoxic T-lymphocyte-associated protein -4 mono clonal Antibody (anti-CTLA-4 mAb) and concurrent local RT in NSCLC patients with metastatic disease.

An open label phase II trial will evaluate the preliminary efficacy of the combination of Ipi and RT, applied to a single metastatic site. Efficacy is measured with respect to systemic tumor responses (abscopal response, outside the field of therapy) defined by immune-related Response Criteria (irRC) in all non-irradiated measurable lesions, as a demonstration of an effective anti-tumor immune response. Secondary endpoints include local response in the RT treated tumor, progression free survival, and overall survival.

Objective 2: Determine the effects of RT and anti-CTLA-4 mAb on development of anti-tumor immunity.

The investigators hypothesize that RT will convert the irradiated tumor into an in situ vaccine and elicit an endogenous tumor-specific cellular and humoral immune response, which in the presence of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade will promote immune-mediated destruction of the irradiated and abscopal metastases. Pre- and post-treatment tumor biopsies will be examined for changes in immune contexture, and blood for evidence of emerging anti-tumor immune responses. Associations with clinical response will be explored.

Study Design

• Study Type: Interventional
• Actual Enrollment: 39 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Combined Ionizing Radiation and Ipilimumab in Metastatic Non-small Cell Lung Cancer (NSCLC)
• Actual Study Start Date: Jul 1, 2014
• Actual Primary Completion Date: Apr 15, 2015
• Actual Study Completion Date: Oct 27, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Ipilimumab + radiotherapy Patients receive ipilimumab (Ipi) 3mg/kg i.v. over 90 minutes, within 24 hours of starting radiotherapy (RT) to the biopsied lesion, 6 Gy x5, later changed to 9.5 Gy x3 (conformally or by intensity modulated RT (IMRT) with image guidance to maximally spare normal tissue). Ipilimumab is repeated on days 22, 43 (for patients who consent to the first biopsy), and 64. Repeat biopsy is performed between day 22-29, and patients are re-imaged between day 81-88 and evaluated for response (defined as an objective response by irRC of the measurable metastatic sites outside the radiation field).

Drug: Ipilimumab; Other Names: Yervoy ; Radiation: Radiotherapy (IMRT or 3-D CRT)

Outcome Measures

Primary Outcome Measures

1. Therapeutic Efficacy of Anti-CTLA-4 mAb and Concurrent Local RT in NSCLC Patients With Metastatic Disease. [3 weeks - 6 months post treatment]

   Tumor Response will be evaluated using the irRC best response (Partial Response (PR) + Complete Response (CR)). Modified WHO criteria will be used for measurement of tumors. The irradiated lesion will be excluded from the assessment of response.

Secondary Outcome Measures

1. Number pf Patients With Objective Radioactive Responses to Measure the Effects of RT and Anti-CTLA-4 mAb on Development of Anti-tumor Immunity Measured by T Cell Clone Frequency [3 weeks - 6 months post-treatment]

   The study uses a comprehensive approach to analyze immunological changes that reflect both local and systemic responses, and investigate both general immune activation as well as tumor antigen-specific T- and B-cell responses. The activity of anti-CTLA-1 mAb is thought to be mainly dependent on modulating the quantity and quality of T-cells in cancer patients. A highly extensive analysis of the Cluster of differentiation 4 + (CD4+) and cluster of differentiation 8 + (CD8+) T-cell subsets will be characterized by multi-color flow Cytometry. To facilitate these analyses, serial blood samples will be collected for serum and peripheral blood mononuclear cells (PBMC) at different time points, where, a part of these samples will be used for DNA/RNA extraction. Optional tissue biopsies will be obtained from consenting patients.Tumor tissue will be tested for expression of seven antigens frequently expressed in NSCLC.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Ability to understand and the willingness to sign a written informed consent document;

2. Histologic diagnosis of metastatic NSCLC;

3. Any Kras or EGFR status is permitted;

4. Patients must have at least two distinct measurable metastatic sites, with one of at least 1 cm or larger in its largest diameter. Patients may have additional non-measurable metastatic lesions (e.g., bone metastases);

5. Patients must have prior treatment with at least one line of therapy for metastatic NSCLC. Any prior therapy is permitted except prior therapy with ipilimumab;

6. An interval of 2 weeks from last previous therapy is required;

7. Patients must have adequate organ and marrow function as defined by initial laboratory tests:

• WBC ≥ 2000/uL

• ANC ≥ 1000/uL

• Platelets ≥ 50 x 103/uL

• Hemoglobin ≥ 8 g/dL

• Creatinine ≤ 3.0 x ULN

• AST/ALT ≤ 2.5 x ULN, or ≤ 5 x ULN if liver metastases are present.

• Bilirubin ≤ 3.0 x ULN (except patients with Gilbert's Syndrome, who must have a total bilirubin ≤ 3.0 mg/dL);

1. Performance status ECOG 0-1;

2. Men and women, ages > 18 years of age;

3. Life expectancy > 3 months;

4. Patients may have brain metastases if these are stable for at least 4 weeks, or greater than 2 weeks post gamma knife therapy and patients are not steroid dependent;

5. Brain Scan (CT/MRI) prior to enrollment

6. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the last dose of Ipi.

Exclusion Criteria:

1. Patients having no lesions outside the field of radiation thus nullifying the ability to measure an abscopal effect;

2. Autoimmune disease: Patients with a history of inflammatory bowel disease are excluded from this study as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, progressive systemic sclerosis [scleroderma]), systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener's granulomatosis];

3. Any underlying medical or psychiatric condition, which in the opinion of the Investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events (AEs), such as a condition associated with frequent diarrhea;

4. Concomitant therapy with any of the following: Interleukin-2 (IL-2), interferon or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids;

5. Prior therapy with ipilimumab or another anti-CTLA-4 antagonist;

6. Women who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 8 weeks after cessation of study drug, or have a positive pregnancy test at baseline, or are pregnant or breastfeeding;

7. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	NYU Clinical Cancer Center	New York	New York	United States	10016
2	NYU Langone Medical Center, Tisch Hospital	New York	New York	United States	10016

Sponsors and Collaborators

• NYU Langone Health
• Bristol-Myers Squibb

Investigators

• Principal Investigator: Abraham Chachoua, MD, NYU School of Medicine

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 4, 2015

More Information

Publications

None provided.

• Responsible Party: NYU Langone Health
• ClinicalTrials.gov Identifier: NCT02221739
• Other Study ID Numbers: 14-00208
• First Posted: Aug 20, 2014
• Last Update Posted: May 11, 2020
• Last Verified: Apr 1, 2020

• 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.: No
• Keywords provided by NYU Langone Health: lung cancer; NSCLC; lung; cancer; radiation; immunotherapy; metastatic
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Ipilimumab

Study Results

Participant Flow

Arm/Group Title	Ipilimumab + Radiotherapy
Arm/Group Description	Patients receive ipilimumab (Ipi) 3mg/kg i.v. over 90 minutes, within 24 hours of starting radiotherapy (RT) to the biopsied lesion, 6 Gy x5, later changed to 9.5 Gy x3 (conformally or by intensity modulated RT (IMRT) with image guidance to maximally spare normal tissue). Ipilimumab is repeated on days 22, 43 (for patients who consent to the first biopsy), and 64. Repeat biopsy is performed between day 22-29, and patients are re-imaged between day 81-88 and evaluated for response (defined as an objective response by irRC of the measurable metastatic sites outside the radiation field). Ipilimumab Radiotherapy (IMRT or 3-D CRT)
Period Title: Overall Study
STARTED	39
COMPLETED	21
NOT COMPLETED	18

Baseline Characteristics

Arm/Group Title	Ipilimumab + Radiotherapy
Arm/Group Description	Patients receive ipilimumab (Ipi) 3mg/kg i.v. over 90 minutes, within 24 hours of starting radiotherapy (RT) to the biopsied lesion, 6 Gy x5, later changed to 9.5 Gy x3 (conformally or by intensity modulated RT (IMRT) with image guidance to maximally spare normal tissue). Ipilimumab is repeated on days 22, 43 (for patients who consent to the first biopsy), and 64. Repeat biopsy is performed between day 22-29, and patients are re-imaged between day 81-88 and evaluated for response (defined as an objective response by irRC of the measurable metastatic sites outside the radiation field). Ipilimumab Radiotherapy (IMRT or 3-D CRT)
Overall Participants	39
Age, Customized (years) [Median (Full Range) ]
Age	68
Sex: Female, Male (Count of Participants)
Female	23 59%
Male	16 41%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (Count of Participants)
United States	39 100%
Histology (Count of Participants)
Adenocarcinoma	34 87.2%
Squamous Cell Carcinoma	3 7.7%
Sarcomatoid	1 2.6%
Neuroendocrine	1 2.6%

Outcome Measures

1. Primary Outcome

Title	Therapeutic Efficacy of Anti-CTLA-4 mAb and Concurrent Local RT in NSCLC Patients With Metastatic Disease.
Description	Tumor Response will be evaluated using the irRC best response (Partial Response (PR) + Complete Response (CR)). Modified WHO criteria will be used for measurement of tumors. The irradiated lesion will be excluded from the assessment of response.
Time Frame	3 weeks - 6 months post treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ipilimumab + Radiotherapy
Arm/Group Description	Patients receive ipilimumab (Ipi) 3mg/kg i.v. over 90 minutes, within 24 hours of starting radiotherapy (RT) to the biopsied lesion, 6 Gy x5, later changed to 9.5 Gy x3 (conformally or by intensity modulated RT (IMRT) with image guidance to maximally spare normal tissue). Ipilimumab is repeated on days 22, 43 (for patients who consent to the first biopsy), and 64. Repeat biopsy is performed between day 22-29, and patients are re-imaged between day 81-88 and evaluated for response (defined as an objective response by irRC of the measurable metastatic sites outside the radiation field). Ipilimumab Radiotherapy (IMRT or 3-D CRT)
Measure Participants	21
Count of Participants [Participants]	7 17.9%

2. Secondary Outcome

Title	Number pf Patients With Objective Radioactive Responses to Measure the Effects of RT and Anti-CTLA-4 mAb on Development of Anti-tumor Immunity Measured by T Cell Clone Frequency
Description	The study uses a comprehensive approach to analyze immunological changes that reflect both local and systemic responses, and investigate both general immune activation as well as tumor antigen-specific T- and B-cell responses. The activity of anti-CTLA-1 mAb is thought to be mainly dependent on modulating the quantity and quality of T-cells in cancer patients. A highly extensive analysis of the Cluster of differentiation 4 + (CD4+) and cluster of differentiation 8 + (CD8+) T-cell subsets will be characterized by multi-color flow Cytometry. To facilitate these analyses, serial blood samples will be collected for serum and peripheral blood mononuclear cells (PBMC) at different time points, where, a part of these samples will be used for DNA/RNA extraction. Optional tissue biopsies will be obtained from consenting patients.Tumor tissue will be tested for expression of seven antigens frequently expressed in NSCLC.
Time Frame	3 weeks - 6 months post-treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ipilimumab + Radiotherapy
Arm/Group Description	Patients receive ipilimumab (Ipi) 3mg/kg i.v. over 90 minutes, within 24 hours of starting radiotherapy (RT) to the biopsied lesion, 6 Gy x5, later changed to 9.5 Gy x3 (conformally or by intensity modulated RT (IMRT) with image guidance to maximally spare normal tissue). Ipilimumab is repeated on days 22, 43 (for patients who consent to the first biopsy), and 64. Repeat biopsy is performed between day 22-29, and patients are re-imaged between day 81-88 and evaluated for response (defined as an objective response by irRC of the measurable metastatic sites outside the radiation field). Ipilimumab Radiotherapy (IMRT or 3-D CRT)
Measure Participants	21
Objective Radiographic Responses	7 17.9%
Complete Responses (CR)	2 5.1%
Partial Responses (PR)	5 12.8%

Adverse Events

Time Frame	60 Months
Adverse Event Reporting Description	Adverse events as related to Ipilimumab or radiotherapy treatment. Grade of adverse event is shown: 1 - mild, 2 - moderate, 3 - Severe or medically significant but not immediately life-threatening, 4 - Life-threatening consequences, and 5 - Death related to AE.
Arm/Group Title	Ipilimumab + Radiotherapy
Arm/Group Description	Patients receive ipilimumab (Ipi) 3mg/kg i.v. over 90 minutes, within 24 hours of starting radiotherapy (RT) to the biopsied lesion, 6 Gy x5, later changed to 9.5 Gy x3 (conformally or by intensity modulated RT (IMRT) with image guidance to maximally spare normal tissue). Ipilimumab is repeated on days 22, 43 (for patients who consent to the first biopsy), and 64. Repeat biopsy is performed between day 22-29, and patients are re-imaged between day 81-88 and evaluated for response (defined as an objective response by irRC of the measurable metastatic sites outside the radiation field). Ipilimumab Radiotherapy (IMRT or 3-D CRT)
All Cause Mortality
	Ipilimumab + Radiotherapy
	Affected / at Risk (%)	# Events
Total	17/39 (43.6%)
Serious Adverse Events
	Ipilimumab + Radiotherapy
	Affected / at Risk (%)	# Events
Total	19/39 (48.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Death	19/39 (48.7%)	19
Other (Not Including Serious) Adverse Events
	Ipilimumab + Radiotherapy
	Affected / at Risk (%)	# Events
Total	39/39 (100%)
Blood and lymphatic system disorders
Anemia	6/39 (15.4%)	6
Hyponatremia	4/39 (10.3%)	4
Hypoxia	2/39 (5.1%)	2
Leukopenia	2/39 (5.1%)	2
Cardiac disorders
Cardiac arrest	2/39 (5.1%)	2
Endocrine disorders
Hyperthyroid	2/39 (5.1%)	2
Hypothyroid	2/39 (5.1%)	2
Gastrointestinal disorders
Abdominal Pain	3/39 (7.7%)	3
Diarrhea	11/39 (28.2%)	11
General disorders
Cough	3/39 (7.7%)	3
Dehydration	3/39 (7.7%)	3
Nausea	5/39 (12.8%)	5
Peripheral neuropathy	3/39 (7.7%)	3
Pruritis	17/39 (43.6%)	17
Rash	13/39 (33.3%)	13
Skin ulceration	2/39 (5.1%)	2
Tachycardia	3/39 (7.7%)	3
Hepatobiliary disorders
Alkaline Phosphotase	6/39 (15.4%)	6
ALT	6/39 (15.4%)	6
AST	5/39 (12.8%)	5
Musculoskeletal and connective tissue disorders
Dry Skin	2/39 (5.1%)	2
Psychiatric disorders
Anorexia	15/39 (38.5%)	15
Dyspnea	9/39 (23.1%)	9
Fatigue	30/39 (76.9%)	30
Fever	3/39 (7.7%)	3
Renal and urinary disorders
Acute Kidney Injury	2/39 (5.1%)	2
Edema	4/39 (10.3%)	4
Hyperglycemia	2/39 (5.1%)	2

Limitations/Caveats

50 dynamic changes of T cell clones in blood were the strongest response predictors, confirming 51 pre-clinical mechanistic data.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.