Radiation and Immune Checkpoints Blockade in Metastatic N... | NCT03168464

NCT03168464

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

Status Module

Name	Class
Bristol-Myers Squibb	INDUSTRY

Description Module

Label	Type	Description	Intervention Names
Immunotherapy + Radiation	Experimental	Non-ablative radiotherapy (6GyX5) is directed to one lesion during a first immunotherapy treatment with Ipilimumab 3 mg/kg (± 24hrs from first RT dose). On day 22 the combined treatment of ipilimumab plus nivolumab will start (nivolumab 240mg q 2 weeks, ipilimumab 1mg/kg q 6 weeks), and administered until evidence of progression.	Drug: Ipilimumab Drug: Nivolumab Radiation: Radiation therapy

Name	Type	Description	Arm Group Labels	Other Names
Ipilimumab	Drug	Ipilimumab (3mg/kg) is given concurrently (+/- 24hrs from first RT dose) with radiation therapy on Day 1 of the study. On day 22 the combined treatment of ipilimumab plus nivolumab will start (nivolumab 240mg q 2 weeks, ipilimumab 1mg/kg q 6 weeks), and administered until evidence of progression.

Measure	Description	Time Frame
Enhance Overall Response Rate (ORR) to the Combination of Ipi/Nivo in Chemo-refractory NSCLC and Double the ORR of Ipi/RT, From 18% Based on Intent to Treat to 36%.	To enhance the ORR to the combination of Ipi/Nivo in chemo-refractory NSCLC by preceding it with a combination of Ipi/RT to convert the irradiated tumor into an in situ vaccine and to double the ORR of Ipi/RT, from 18% based on intent to treat to 36%.	2.5 Months, 6 Months, 3 years

Measure	Description	Time Frame
Changes in T-cell Receptor (TCR) Repertoire in Peripheral Blood Are Associated With Response to Treatment	changes in T-cell receptor (TCR) repertoire in peripheral blood are associated with response to treatment	4 years
Serum Markers IFN-b, CXCL11, sMICA, sMICB Levels/Changes Associated With Patients' Response to the Treatment.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Ability to understand and the willingness to sign a written informed consent document;
Histologic diagnosis of NSCLC;
Any Kras or epidermal growth factor receptor (EGFR) status is permitted; Patients with an EGFR sensitizing mutation must have received an EGFR tyrosine kinase inhibitor (either erlotinib, gefitinib or afatinib) and patients with anaplastic lymphoma kinase (ALK) translocation must have received anti-ALK therapy.
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);
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, other anti cytotoxic T-lymphocyte-associated protein (CTLA) agents or Checkpoint inhibitors;
An interval of 2 weeks from last previous therapy is required;
Patients must have recovered from the toxic effect(s) of the most recent anti-cancer treatment to NCI CTCAE Grade 1 or less (except alopecia).
Patients must have adequate organ and marrow function as defined by initial laboratory tests:

white blood cell (WBC) ≥ 2000/uL

absolute neutrophil count (ANC) ≥ 1.5/uL
Platelets ≥ 100 x 103/uL
Hemoglobin ≥ 9 g/dL
Creatinine ≤ 1.5 x upper limit of normal (ULN)
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 x ULN, or ≤ 5 x ULN if liver metastases are present.
Bilirubin ≤ 1.5 x ULN, (except patients with Gilbert's Syndrome, who must have a total bilirubin ≤ 3.0 mg/dL;
- Performance status Eastern Cooperative Oncology Group (ECOG) 0-1 or Karnofsky > 70%;
- Men and women, ages > 18 years of age;
- Life expectancy > 3 months;
- Patients may have brain metastases if these are stable for at least 4 weeks and patients are not steroid dependent;
- 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 study.
WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal [defined as amenorrhea ≥ 12 consecutive months; or women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL ]. Even women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g., vasectomy), should be considered to be of child bearing potential. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin (hCG)) within 72 hours prior to the start of study medication.Men should use avoid impregnating women during study and for 7 mos after the study.

Exclusion Criteria:

Patients having no lesions outside the field of radiation thus nullifying the ability to measure an abscopal effect;
Autoimmune disease: Patients with a history of inflammatory bowel disease are excluded from this study as are patients with a history of symptomatic auto immune disease (e.g., rheumatoid arthritis, progressive systemic sclerosis [scleroderma]), systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener's granulomatosis];
Patients with a history of symptomatic interstitial lung disease OR a history of (non-infectious) pneumonitis that required oral or IV steroids or current pneumonitis.
Patients with active HIV infection Patients with Hepatitis B and Hepatitis C infection.
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;
Concomitant therapy with any of the following: IL-2, interferon or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids; Tyrosine Kinase inhibitors such as erlotinib;
Prior therapy with ipilimumab or another anti-CTLA-4 antagonist;
Women and men who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 5mos (women) or 7mos(men) weeks after cessation of study drug, or have a positive pregnancy test at baseline, or are pregnant or breastfeeding;
Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness.

Name	Affiliation	Role
Silvia Formenti, M.D.	Weill Cornell Medicine New York Prebyterian hospital	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Weill Cornell Medicine		New York	New York	10065	United States

Arm/Group Information

ID	Title	Description
FG000	Immunotherapy + Radiation	Non-ablative radiotherapy (6GyX5) is directed to one lesion during a first immunotherapy treatment with Ipilimumab 3 mg/kg (± 24hrs from first RT dose). On day 22 the combined treatment of ipilimumab plus nivolumab will start (nivolumab 240mg q 2 weeks, ipilimumab 1mg/kg q 6 weeks), and administered until evidence of progression. Ipilimumab: Ipilimumab (3mg/kg) is given concurrently (+/- 24hrs from first RT dose) with radiation therapy on Day 1 of the study. On day 22 the combined treatment of ipilimumab plus nivolumab will start (nivolumab 240mg q 2 weeks, ipilimumab 1mg/kg q 6 weeks), and administered until evidence of progression. Nivolumab: On day 22 the combined treatment of ipilimumab plus nivolumab will start (nivolumab 240mg q 2 weeks, ipilimumab 1mg/kg q 6 weeks), and administered until evidence of progression. Radiation therapy: Ipilimumab (3mg/kg) is given concurrently (+/- 24hrs from first RT dose) with radiation therapy on Day 1 of the study.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Immunotherapy + Radiation	Non-ablative radiotherapy (6GyX5) is directed to one lesion during a first immunotherapy treatment with Ipilimumab 3 mg/kg (± 24hrs from first RT dose). On day 22 the combined treatment of ipilimumab plus nivolumab will start (nivolumab 240mg q 2 weeks, ipilimumab 1mg/kg q 6 weeks), and administered until evidence of progression. Ipilimumab: Ipilimumab (3mg/kg) is given concurrently (+/- 24hrs from first RT dose) with radiation therapy on Day 1 of the study. On day 22 the combined treatment of ipilimumab plus nivolumab will start (nivolumab 240mg q 2 weeks, ipilimumab 1mg/kg q 6 weeks), and administered until evidence of progression. Nivolumab: On day 22 the combined treatment of ipilimumab plus nivolumab will start (nivolumab 240mg q 2 weeks, ipilimumab 1mg/kg q 6 weeks), and administered until evidence of progression. Radiation therapy: Ipilimumab (3mg/kg) is given concurrently (+/- 24hrs from first RT dose) with radiation therapy on Day 1 of the study.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Enhance Overall Response Rate (ORR) to the Combination of Ipi/Nivo in Chemo-refractory NSCLC and Double the ORR of Ipi/RT, From 18% Based on Intent to Treat to 36%.

To enhance the ORR to the combination of Ipi/Nivo in chemo-refractory NSCLC by preceding it with a combination of Ipi/RT to convert the irradiated tumor into an in situ vaccine and to double the ORR of Ipi/RT, from 18% based on intent to treat to 36%.

Participants were not assessed at 3 years.

Posted

Count of Participants

Participants

2.5 Months, 6 Months, 3 years

ID	Title	Description
OG000	Immunotherapy + Radiation	Non-ablative radiotherapy (6GyX5) is directed to one lesion during a first immunotherapy treatment with Ipilimumab 3 mg/kg (± 24hrs from first RT dose). On day 22 the combined treatment of ipilimumab plus nivolumab will start (nivolumab 240mg q 2 weeks, ipilimumab 1mg/kg q 6 weeks), and administered until evidence of progression. Ipilimumab: Ipilimumab (3mg/kg) is given concurrently (+/- 24hrs from first RT dose) with radiation therapy on Day 1 of the study. On day 22 the combined treatment of ipilimumab plus nivolumab will start (nivolumab 240mg q 2 weeks, ipilimumab 1mg/kg q 6 weeks), and administered until evidence of progression. Nivolumab: On day 22 the combined treatment of ipilimumab plus nivolumab will start (nivolumab 240mg q 2 weeks, ipilimumab 1mg/kg q 6 weeks), and administered until evidence of progression. Radiation therapy: Ipilimumab (3mg/kg) is given concurrently (+/- 24hrs from first RT dose) with radiation therapy on Day 1 of the study.

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Immunotherapy + Radiation	Non-ablative radiotherapy (6GyX5) is directed to one lesion during a first immunotherapy treatment with Ipilimumab 3 mg/kg (± 24hrs from first RT dose). On day 22 the combined treatment of ipilimumab plus nivolumab will start (nivolumab 240mg q 2 weeks, ipilimumab 1mg/kg q 6 weeks), and administered until evidence of progression. Ipilimumab: Ipilimumab (3mg/kg) is given concurrently (+/- 24hrs from first RT dose) with radiation therapy on Day 1 of the study. On day 22 the combined treatment of ipilimumab plus nivolumab will start (nivolumab 240mg q 2 weeks, ipilimumab 1mg/kg q 6 weeks), and administered until evidence of progression. Nivolumab: On day 22 the combined treatment of ipilimumab plus nivolumab will start (nivolumab 240mg q 2 weeks, ipilimumab 1mg/kg q 6 weeks), and administered until evidence of progression. Radiation therapy: Ipilimumab (3mg/kg) is given concurrently (+/- 24hrs from first RT dose) with radiation therapy on Day 1 of the study.

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Shortness of breath	Respiratory, thoracic and mediastinal disorders	CTCAE 5.0	Systematic Assessment	Shortness of breath

ID	Term
D061067	Antibodies, Monoclonal, Humanized
D000911	Antibodies, Monoclonal
D000906	Antibodies
D007136	Immunoglobulins

ID	Term
D000074324	Ipilimumab
D000077594	Nivolumab
D011878	Radiotherapy