Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05088889 |
| Other study ID # |
CA184-604 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 1
|
| First received |
|
| Last updated |
|
| Start date |
January 25, 2022 |
| Est. completion date |
July 1, 2024 |
Study information
| Verified date |
November 2023 |
| Source |
Sheba Medical Center |
| Contact |
Talia Golan, Prof. |
| Phone |
972545774869 |
| Email |
Talia.Golan[@]sheba.health.gov.il |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
In this study we aim to test the efficacy of a combined and novel approach including
induction chemotherapy (per standard of care) followed by SBRT and maintenance ipililumab +
nivolumab in the first line setting of stage IV PDAC.
Study Hypothesis:
Cytotoxic chemotherapy followed by hypofractionated radiotherapy will sensitize pancreatic
cancer to immunotherapy consisting of combined PD-1 and CTLA4 blockade. We hypothesize that
direct targeting of the pancreatic cancer cells by chemotherapy and hypofractionated
radiotherapy is necessary for initial anti-tumor response. Furthermore, the combination of
immunotherapy as a maintenance strategy will have profound anti-tumor efficacy in this
setting.
Implications of hypothesis:
- Improved response rate above historical controls
- Lengthened progression-free survival
- Improved overall-survival
Exploratory Hypothesis:
We hypothesize that baseline markers of immune activation such as Tumor Infiltrating
Lymphocytes and CD8+ lymphocytes will correlate with response to ipililumab + nivolumab and
that responders will have distinct tumor immune phenotype as determined by
immunohistochemistry and gene expression profiling compared to nonresponders.
Description:
This is a single arm, single institution study, which aims to evaluate the efficacy and
safety of combination therapy with radiosurgery nivolumab and ipilimumab as a maintenance
regimen following first line induction chemotherapy in patients with metastatic pancreatic
cancer.
Chemotherapy will be administrated for a minimum of 4 cycles. Patients who have not
progressed on chemotherapy will receive SBRT to one primary/metastatic tumor, followed by
ipilimumab (1mg/kg every six weeks) + nivolumab (360mg every three weeks). After a further 8
weeks patients will be assessed for response; responders will continue ipilimumab + nivolumab
until disease progression, non-responders will receive very low dose radiation to metastatic
sites (this will only be allowed once) prior to continuing ipilimumab + nivolumab until
disease progression. Immunotherapy will be continued until disease progression or up to 24
months in the absence of disease progression or unacceptable toxicity.
Study rationale Overall rational in Brief Although there is evidence for that the immune
system plays an active role in pancreatic cancer, until now checkpoint inhibitors have yet to
demonstrate efficacy in this population. We hypothesize that combining irradiation along with
checkpoint inhibition in a patient population demonstrating stable disease in a first line
setting will be a novel approach towards the treatment of pancreatic cancer.
Rationale for Combining Nivolumab and Ipilimumab The roles of CTLA-4 and PD-1 in inhibiting
antitumor responses are largely distinct. Whereas CTLA-4 is thought to regulate T-cell
proliferation early in the immune response, primarily in lymph nodes, PD-1 suppresses T cells
at a later stage in the immune response, primarily in peripheral tissues.
Preclinical data indicate that the combination of PD-1 and CTLA-4 receptor blockade may
improve antitumor activity.
Encouraging response rates for the combination of nivolumab and ipilimumab have been
demonstrated in several types of cancer such as melanoma, renal cell carcinoma, and non-small
cell lung cancer.
Due to toxicity concerns regarding the combination of nivolumab and ipilimumab, several
different doses and schedules were evaluated in a phase 1 study as first-line therapy in
patients with advanced NSCLC (CA209012). This study identified an alternative schedule with
an acceptable tolerability profile (28% grade 3-4 toxicity) and encouraging activity (31%
overall response rate) - nivolumab 360 mg/kg every 3 weeks plus ipilimumab 1 mg/kg every 6
weeks, and has therefore been adopted in this protocol.
Rationale for Combining Radiosurgery with anti-PD-1 and anti-CTLA-4 High-dose radiation (such
as used in stereotactic radiation body therapy - SBRT) induces DNA damage and cell death.
Radiation alone appears to induce a systemic immune response.
The biologic rationale behind the strategy is that radiation will cause release of
immunogenic tumor-antigens from dying tumor cells, which will be processed by cells of the
adaptive immune system, eventually promoting tumor-specific targeting of the tumor by the
immune system. Success of this strategy will hopefully induce and augment the rarely seen
abscopal effect. One possible explanation is that radiation alone rarely induces a rich
immune infiltrate into the dying tumor.
Radiation dose and fractionation schedules for optimal synergy between radiotherapy and
immunotherapy are not well defined. Three fractions of 8 Gy has been successfully combined
with anti-CTLA-4 therapy in mice, and has emerged as a popular regimen for radiation -
immunotherapy trials, and has therefore been adopted in this protocol.
Study Population Estimated accrual - 10 patients. The patients for the study will be
identified from the pancreatic cancer clinics at Sheba Medical Center with advanced
pancreatic cancer (stage IV) in the first-line setting.
Approximately 17 patients will be initially evaluated in the first line setting. We estimate
that approximately 50-60% will not progress at three months and they will continue to receive
the study treatment. Only the non-progressors who receive SBRT and combination immunotherapy
will be evaluated in the ITT population.
TREATMENT PLAN:
Stereotactic radiosurgery Simulation will be performed in accordance with the target lesion
location, with 3D or 4D CT as appropriate. Three fractions of 8 Gy, treated on alternate days
(in exceptional circumstances, may treat on consecutive days).
Nivolumab and Ipilimumab Nivolumab administered IV over 30 minutes at a dose of 360mg every 3
weeks. Ipilimumab administered IV over 30 minutes at 1 mg/kg every 6 weeks following the
administration of nivolumab. On the day of infusion, nivolumab is to be administered first.
Ipilimumab will start at least 30 minutes after completion of the nivolumab infusion.
Nivolumab and ipilimumab will be continued until the progression of disease, discontinuation
due to toxicity, withdrawal of consent, or study closure. In any event medication will not be
continued beyond 24 months. Subjects may discontinue only ipilimumab and continue treatment
with nivolumab if certain circumstances are met. Treatment beyond initial investigator
assessed RECIST v1.1 defined progression 2 is permitted if the subject has investigator
assessed clinical benefit and is tolerating nivolumab and ipilimumab.
Low dose irradiation at first progression At time of 1st progression, at physician's
discretion, a single fraction of low dose irradiation (2Gy) will be given to the metastatic
lesions. These patients will continue with immunotherapy - Nivolumab and Ipilimumab in
accordance with treatment protocol. Approximately one week prior to irradiation a simulation
scan will be required. The extent of the low radiation field will depend on the number and
location of the metastases, as well as the feasibility and safety of the treatment.
Duration of Therapy
In the absence of treatment delays due to adverse event(s), treatment may continue until one
of the following criteria applies:
- Second disease progression
- Intercurrent illness that prevents further administration of treatment
- Unacceptable adverse event(s)
- Patient decides to withdraw from the study
- General or specific changes in the patient's condition render the patient unacceptable
for further treatment in the judgment of the investigator
- Clinical progression
- Patient non-compliance
- Pregnancy
- Termination of the study by sponsor
- The drug manufacturer can no longer provide the study agent
- In any event medication will not be continued beyond 24 months.
Duration of Follow-Up After removal from study treatment patients will return to the clinic
for a short-term FU visit 28 days after the last dose of study treatment.
First long term FU should be performed 100days after the last dose of study drug, and every
90 days thereafter, until death, termination of the study or withdrawal of consent, whichever
occurs first. In addition, patients in survival follow-up will be contacted following the
data cut-off for the primary analysis and all subsequent survival analyses to provide
complete survival data. These contacts should generally occur within 7 days of the data cut
off.
- All patients who start the study treatments should be followed up.
- information may be obtained via telephone contact, patient's notes, or public records.
- If the site becomes aware that a patient has died prior to the final analysis, data
should be completed at that time.
- Patients who discontinue treatment prior to progression should continue to have RECIST
assessments (every 8 weeks from starting study treatment), until confirmed objective
disease progression, as defined by RECIST 1.1.
Dose Delay Criteria: Tumor assessments for all subjects should continue as per protocol even
if dosing is delayed.
Nivolumab and ipilimumab administration should be delayed for the following:
- Any Grade ≥ 2 non-skin, drug-related adverse event, except for fatigue and laboratory
abnormalities
- Any Grade ≥ 3 skin drug-related AE
- Any Grade ≥ 3 drug-related laboratory abnormality with the following exceptions for
lymphopenia, AST, ALT, or total bilirubin or asymptomatic amylase or lipase:
- Grade 3 lymphopenia does not require a dose delay
- If a subject has a baseline AST, ALT, or total bilirubin that is within normal
limits, delay dosing for drug-related Grade ≥ 2 toxicity
- If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity
range, delay dosing for drug-related Grade ≥ 3 toxicity
- Any Grade ≥ 3 drug-related amylase or lipase abnormality that is not associated
with symptoms or clinical manifestations of pancreatitis does not require dose
delay. The Principal Investigator should be consulted for such Grade ≥ 3 amylase or
lipase abnormalities.
- Any AE, laboratory abnormality or inter-current illness which, in the judgment of the
investigator, warrants delaying the dose of study medication.
Subjects receiving ipilimumab in combination with nivolumab that have drug-related toxicities
that meet the criteria for dose delay, should have both drugs (ipilimumab and nivolumab)
delayed until retreatment criteria are met. Exceptions apply to the retreatment criteria
after dose delay of ipilimumab and nivolumab for Grade ≥ 3 amylase and lipase abnormalities
that are not associated with symptoms or clinical manifestations of pancreatitis and that are
attributed to ipilimumab alone.
Rescheduling
- Nivolumab may be delayed until the next planned ipilimumab dose if the next ipilimumab
dose is scheduled within the next 12 days. This will permit periodic ipilimumab dosing
to be synchronized with nivolumab dosing.
- Ipilimumab should be dosed at the specified interval regardless of any delays in
intervening nivolumab doses. However, in order to maintain periodic synchronized dosing
of ipilimumab and nivolumab, the dosing days of nivolumab and ipilimumab may be adjusted
within the permitted +/- 5 day window, as long as consecutive nivolumab doses are given
at least 12 days apart. Ipilimumab may be delayed beyond the 5 day window if needed to
synchronize with the next nivolumab dose.
- If an ipilimumab dose is delayed beyond 6 weeks from the prior ipilimumab dose, then
subsequent ipilimumab doses should rescheduled to maintain the 6 week interval between
consecutive ipilimumab doses. Ipilimumab may not be resumed sooner than 6 weeks (+/-
5days) after the prior ipilimumab dose.
- A dose delay of ipilimumab which results in no ipilimumab dosing for > 12 weeks requires
ipilimumab discontinuation, with exceptions as noted in study protocol.
- Dose delay of nivolumab which results in treatment interruption of > 6 weeks requires
treatment discontinuation, with exceptions as noted
Dose reductions There will be no dose reductions for nivolumab or ipilimumab.
Criteria to Resume Dosing
Subjects may resume treatment with nivolumab and/or ipilimumab when the drug-related AE(s)
resolve(s) to Grade ≤ 1 or baseline, with the following exceptions:
- Subjects may resume treatment in the presence of Grade 2 fatigue.
- Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in
the presence of Grade 2 skin toxicity.
- Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for
reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in
the presence of Grade 2 AST/ALT OR total bilirubin.
- Subjects with combined Grade 2 AST/ALT and total bilirubin values meeting
discontinuation parameters should have treatment permanently discontinued.
- Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline
before treatment is resumed.
- For Nivolumab: Subjects with persistent Grade 1 pneumonitis after completion of a
steroid taper over at least 1 month may be eligible for retreatment if discussed with
and approved by the Principal Investigator.
- Subjects who received systemic corticosteroids for management of any drug-related
toxicity must be off corticosteroids or have tapered down to an equivalent dose of
prednisone ≤ 10 mg/day.
- Drug-related endocrinopathies adequately controlled with only physiologic hormone
replacement may resume treatment after consultation with the Principal Investigator.
- In general, subjects who meet criteria to resume ipilimumab will also have met criteria
to resume nivolumab, so it should be feasible to synchronize dosing of both drugs when
resuming ipilimumab. In order to facilitate this, the dosing days of nivolumab and
ipilimumab may be adjusted within the permitted +/- 5 day window, as long as consecutive
nivolumab doses are given at least 12 days apart.
- One exception to note is when ipilimumab and nivolumab doses are delayed due to drug
related Grade ≥ 3 amylase or lipase abnormalities not associated with symptoms or
clinical manifestations of pancreatitis. If the investigator assesses the amylase or
lipase abnormality to be related to ipilimumab and not related to nivolumab, nivolumab
may be resumed when the amylase or lipase abnormality resolves to Grade < 3 but
ipilimumab may only be resumed when the amylase or lipase abnormality resolves to Grade
1 or baseline. Investigator attribution of this toxicity to the ipilimumab dosing must
be clearly noted in the subject's medical chart. The Principal Investigator should be
consulted prior to resuming nivolumab in such subjects
Nivolumab Treatment Discontinuation Criteria:
- Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to
topical therapy and does not improve to Grade 1 severity within the re-treatment period
OR requires systemic treatment.
- Any Grade ≥ 2 drug-related pneumonitis or interstitial lung disease that does not
resolve to dose delay and systemic steroids (also see Pulmonary Adverse Event Management
Algorithm).
- Any Grade 3 drug-related bronchospasm, hypersensitivity reaction, or infusion reaction,
regardless of duration.
- Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following
exceptions for uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic
toxicity, hypersensitivity reactions, infusion reactions, endocrinopathies, and
laboratory abnormalities:
- Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis,
neurologic toxicity, hypersensitivity reaction, or infusion reaction of any
duration requires discontinuation.
- Grade 3 drug-related endocrinopathies adequately controlled with only physiologic
hormone replacement do not require discontinuation.
- Grade 3 drug-related laboratory abnormalities do not require treatment
discontinuation except:
- Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires
discontinuation.
- Any drug-related liver function test (LFT) abnormality that meets the following
criteria require discontinuation (also see Hepatic Adverse Event Management
Algorithm):
- AST or ALT > 5-10 x ULN for > 2 weeks
- Total bilirubin > 5 x ULN
- Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
- Any Grade 4 drug-related adverse event or laboratory abnormality, except for the
following events, which do not require discontinuation:
- Grade 4 neutropenia ≤ 7 days
- Grade 4 lymphopenia or leukopenia
- Isolated Grade 4 amylase or lipase abnormalities that are not associated with
symptoms or clinical manifestations of pancreatitis and decrease to < Grade 4
within 1 week of onset. The Principal Investigator should be consulted for Grade 4
amylase or lipase abnormalities
- Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with
clinical sequelae and are corrected with supplementation/appropriate management
within 72 hours of their onset
- Grade 4 drug-related endocrinopathy adverse events such as adrenal insufficiency,
ACTH deficiency, hyper- or hypothyroidism, or glucose intolerance, which resolve or
are adequately controlled with physiologic hormone replacement (corticosteroids,
thyroid hormones) or glucose controlling agents, respectively, may not require
discontinuation after discussion with and approval from the Principal Investigator.
- Dosing delays lasting > 6 weeks that occur for non-drug-related reasons may be
allowed if approved by the Principal Investigator. Periodic study visits to assess
safety and laboratory studies should also continue every 6 weeks or more frequently
if clinically indicated during such dosing delays.
- Any adverse event, laboratory abnormality, or intercurrent illness which, in the
judgment of the Investigator, presents a substantial clinical risk to the subject with
continued ivolumab dosing.
If discontinuation criteria are met for ipilimumab but not for nivolumab, treatment with
nivolumab may continue.
Ipilimumab Treatment Discontinuation Criteria:
- Any Grade ≥ 2 drug-related uveitis or eye pain or blurred vision that does not respond
to topical therapy and does not improve to Grade 1 severity within 2 weeks OR requires
systemic treatment.
- Any Grade ≥3 bronchospasm or other hypersensitivity reaction.
- Any other Grade 3 non-skin, drug-related adverse with the following exceptions for
laboratory abnormalities, grade 3 nausea and vomiting, grade 3 neutropenia and
thrombocytopenia, and symptomatic endocrinopathies which resolved (with or without
hormone substitution).
- Any drug-related liver function test (LFT) abnormality that meets the following criteria
require discontinuation:
AST or ALT > 8 x ULN Total bilirubin > 5 x ULN Concurrent AST or ALT > 3 x ULN and total
bilirubin > 2 x ULN
- Any Grade 4 drug-related adverse event or laboratory abnormality, except for the
following events, which do not require discontinuation:
- Grade 4 neutropenia ≤ 7 days
- Grade 4 lymphopenia or leukopenia
- Isolated Grade 4 amylase or lipase abnormalities which are not associated with
symptoms or clinical manifestations of pancreatitis.
- Isolated Grade 4 electrolyte abnormalities that are not associated with clinical
sequelae and are corrected with appropriate management within 72 hours of their
onset
- Grade 4 drug-related endocrinopathy adverse events such as adrenal insufficiency,
ACTH deficiency, hyper- or hypothyroidism, or glucose intolerance, which resolve or
are adequately controlled with physiologic hormone replacement or glucose
controlling agents, respectively, may not require discontinuation after discussion
with the Principal Investigator.
- Dosing delays resulting in no ipilimumab dosing for > 12 weeks that occur for
non-drug-related reasons may be allowed if approved by the Principal Investigator.
- Any adverse event, laboratory abnormality, or intercurrent illness which, in the
judgment of the Investigator, presents a substantial clinical risk to the subject with
continued ipilimumab dosing
Treatment Beyond Disease Progression 2
Subjects will be permitted to continue on nivolumab and ipilimumab for treatment beyond
initial RECIST v1.1 defined PD as long as they meet the following criteria:
- Investigator-assessed clinical benefit and no rapid disease progression
- Subject is tolerating study treatment
- Stable performance status
- Treatment beyond progression will not delay an imminent intervention to prevent serious
complications of disease progression (e.g., CNS metastases) A follow-up scan should be
performed within 4 weeks ±5 days of original PD to determine whether there has been a
continued progression of disease. Subsequent scans should be performed every 8 weeks
until further progression is determined.
Study treatment should be discontinued permanently upon further progression.
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS AEs will be graded and recorded throughout
the trial and during the follow-up period according to NCI CTCAE Version 5.0. Toxicities will
be characterized in terms regarding seriousness, causality, toxicity grading, and action
taken with regard to trial treatment.
Identifying the adverse event:
Any inflammatory event, especially those that may respond to steroids, should be considered a
possible adverse event. Most such events cannot be identified on physical examination. It
should be appreciated that patients may not report these symptoms, or may present to other
specialists, who may give inappropriate treatment, e.g potent anti-diarrheal to control a
resistant diarrhea. Furthermore, physicians should be aware that some side effects may appear
many weeks after treatment initiation.
Early diagnosis and treatment intervention for inflammatory events can help prevent the
occurrence of complications, such as GI perforation. Toxicities related to GI (diarrhea and
colitis) and skin (rash and pruritus) are the most common inflammatory events reported in
studies with ipilimumab.
The combination of both Nivolumab+ipilimumab results in a safety profile with similar types
of AEs as either agent alone, but in some cases, with a greater frequency. In general, dose
delays and observation are adequate for low-grade AEs. For moderate- and high-grade AEs,
immunosuppression with corticosteroids should be utilized. Once the AE has begun to improve,
corticosteroids can be tapered over approximately 3 weeks to 6 weeks (depending on the
severity of the AE). The management of AEs considered related to any combination treatment is
similar to the management of AEs caused by either agent alone and utilizes the same safety
management algorithms.
Patients should be assessed for signs and symptoms of enterocolitis, dermatitis, neuropathy,
and endocrinopathy; and clinical chemistries (including liver function and thyroid function
tests) should be evaluated at baseline and at regular intervals.
Overview of management of adverse event Aside from very mild side effects, the first step
should be to hold all study immunotherapies. Early intervention with steroids is to be
considered in the majority of cases, followed possibly by re-starting the study therapeutic
agents.
During evaluation of a suspected immune-mediated AE, all efforts should be made to rule out
neoplastic, infectious, metabolic, toxic, or other etiologic causes. Serological,
immunological, imaging, and occasionally biopsy with histology (e.g., biopsy-proven
lymphocytic) data may be used to support the diagnosis of an immune-mediated toxicity or
support an alternative cause of the AE.
In general, for severe immune-mediated AEs, nivolumab and/or ipilimumab should be permanently
discontinued, and systematic high-dose corticosteroid therapy should be initiated. For
moderate immune-mediated AEs, ipilimumab should be held or delayed, and moderate-dose
corticosteroids should be considered. Upon improvement, corticosteroids should be tapered
gradually over at least 1 month.
The causal relationship to study drug is determined by a physician and should be used to
assess all adverse events (AE).
Definition of Serious Adverse Event Serious events include, but are not limited to, intensive
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or
convulsions that do not result in hospitalization.) Potential drug induced liver injury
(DILI) is also considered an important medical event.
Suspected transmission of an infectious agent via the study drug is an SAE. Although
pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not always
serious by regulatory definition, these events must be handled as SAEs. Any component of a
study endpoint that is considered related to study therapy should be reported as SAE.
NOTE: The following hospitalizations are not considered SAEs:
- a visit to the emergency room or other hospital department < 24 hours
- elective surgery, planned prior to signing consent
- routine health assessment requiring admission for baseline/trending of health status
(eg, routine colonoscopy).
- Medical/surgical admission other than to remedy ill health and planned prior to entry
into the study.
- Admission encountered for another life circumstance that carries no bearing on health
status and requires no medical/surgical intervention.
- Admission for administration of anticancer therapy in the absence of any other SAEs
(applies to oncology protocols)
Serious Adverse Event Collection and Reporting All SAEs must be collected that occur during
the screening period and within 100 days of the last dose of study drug. Subjects, who are
randomized and never treated with study drug, must have SAEs collected for 30 days from the
date of randomization. If applicable, SAEs that relate to any later protocol-specified
procedure (eg, a follow-up skin biopsy) must be collected.
The investigator should report any SAE that occurs after these time periods and that is
believed to be related to study drug or protocol-specified procedure.
An SAE report should be completed for any event where doubt exists regarding its seriousness.
If the investigator believes that an SAE is potentially related to the conditions of the
study (such as withdrawal of previous therapy or a complication of a study procedure), the
relationship should be specified.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS
(or designee) within 24 hours of awareness of event. SAEs must be recorded on the SAE Report
Form; pregnancies on a Pregnancy Surveillance Form. Paper forms are to be transmitted via
email or confirmed facsimile (fax). In addition, the local IRB will be informed per local
regulations.
If only limited information is initially available, follow-up reports are required. (Note:
Follow-up SAE reports should include the same investigator term(s) initially reported.) If an
ongoing SAE changes in its intensity or relationship to study drug or if new information
becomes available, a follow-up SAE report should be sent within 24 hours to BMS (or designee)
using the same procedure.
All SAEs should be followed to resolution or stabilization. The Investigator will request
from BMS the SAE reconciliation report and include the BMS protocol number every 3 months and
prior to data base lock or final data summary.
Nonserious Adverse Event Collection and Reporting The collection of non-serious AE
information should begin following the subject's written consent to participate in the study
And should be followed to resolution or stabilization of the adverse event to grade 1, or
reported as SAEs if they become serious. Follow-up is also required for nonserious AEs that
cause interruption or discontinuation of study drug and for those present at the end of study
treatment as appropriate. All AEs must be recorded on the CRF.
All nonserious adverse events are to be collected continuously during the treatment period
and for a minimum of 28 days following the last dose of study treatment.
Pregnancy Investigator must immediately notify BMS of Pregnancy event and complete and
forward a Pregnancy Surveillance Form within 24 hours of awareness of the event and in
accordance with SAE reporting procedures.
In the rare event that the benefit of continuing study drug is thought to outweigh the risk,
the pregnant subject may continue study drug after a thorough discussion, if allowed by local
regulations.
Protocol-required procedures for study discontinuation and follow-up must be performed on the
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy
follow-up procedures should be considered if indicated.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal
outcome and, where applicable, offspring information must be reported on the Pregnancy
Surveillance Form.
Men receiving nivolumab and who are sexually active with women of childbearing potential will
be instructed to adhere to contraception for a period of 7 months after the last dose of
nivolumab.
In order to collect any pregnancy surveillance information from the female partner, the
female partner must sign an informed consent form for disclosure of this information.
Information on this pregnancy will be collected on the Pregnancy Surveillance Form and
reported to BMS.
Overdose An overdose is defined as the accidental or intentional administration of any dose
of a product that is considered both excessive and medically important. All occurrences of
overdose must be reported as SAEs.
Potential Drug Induced Liver Injury (DILI) All occurrences of potential DILIs, meeting the
defined criteria, must be reported as SAEs .
Potential DILI is defined as: ALT or AST elevation > 3 times upper limit of normal (ULN) AND
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum
alkaline phosphatase), AND No other immediately causes of AT elevation and
hyperbilirubinemia.
A hepatic AE management algorithm has been established (and is indicated in the protocol).
CORRELATIVE STUDIES During IO therapy Blood, Stool and Saliva samples for correlative study
will be taken cycle 1 Day 1 of and every 8 weeks thereafter. Biopsies of the disease lesion
will be obtained prior to start of treatment and at 8 weeks. Specific permission will
therefore be included in the consent form. Local regulations for tissue banking and storage
will be followed.
Fresh biopsy specimens from disease lesion during screening (preferably, at site of SBRT) and
at 8 weeks imaging assessment are mandatory. Optional tissue biopsy will be requested at
progression. (For patients that have stopped treatment for other reasons than PD, tissue
biopsy will be requested at the time of PD.
In addition, Tissue samples will be submitted from existing archived biopsy (diagnostic
specimen), if available.
STATISTICAL CONSIDERATIONS
Study populations will include safety and efficacy:
- Safety Population will include all subjects who receive at least 1 dose of ipilimumab,
nivolumab.
- Efficacy population will include all subjects in the Safety Population with at least 1
recorded post-baseline disease assessment Statistical methods will be primarily
descriptive in nature. Categorical variables will be summarized using numbers and
percentages. Continuous variables will be summarized by total number (n), mean, standard
deviation, median, and range (minimum and maximum).
Event rates will be summarized, and Kaplan-Meier estimates for PFS and OS may also be
provided where sample size is adequate.
Safety data, including vital signs, laboratory test results, physical examinations, and
adverse events (AEs), will be summarized by dose and assessment time points, as appropriate.
Change from baseline will be included in summary tables for laboratory, and vital sign
parameters.
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