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Trial details imported from

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Registration number
Ethics application status
Date submitted
Date registered
Date last updated

Titles & IDs
Public title
A Phase II Trial of Ipilimumab and Nivolumab for the Treatment of Rare Cancers
Scientific title
A Phase II Clinical Trial Evaluating Ipilimumab and Nivolumab in Combination for the Treatment of Rare Gastrointestinal, Neuro-Endocrine and Gynaecological Cancers
Secondary ID [1] 0 0
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Gastrointestinal Cancer 0 0
Neuroendocrine Tumours 0 0
Malignant Female Reproductive System Neoplasm 0 0
Condition category
Condition code
Cancer 0 0 0 0
Neuroendocrine tumour (NET)
Cancer 0 0 0 0
Other cancer types
Oral and Gastrointestinal 0 0 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Cancer 0 0 0 0
Ovarian and primary peritoneal
Cancer 0 0 0 0
Womb (Uterine or endometrial cancer)
Cancer 0 0 0 0
Cervical (cervix)

Study type
Description of intervention(s) / exposure
Treatment: Drugs - Ipilimumab
Treatment: Drugs - Nivolumab

Experimental: Ipilimumab and Nivolumab - All Subjects will be treated with: Nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg concurrently every 3 weeks for 4 doses followed by nivolumab only at 3mg/kg every 2 weeks until progression (up to 48 total doses of nivolumab)

Treatment: Drugs: Ipilimumab
CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) is a key regulator of T cell activity. Ipilimumab is a CTLA-4 immune checkpoint inhibitor that blocks T-cell inhibitory signals induced by the CTLA-4 pathway, increasing the number of tumor reactive T effector cells which mobilize to mount a direct T-cell immune attack against tumor cells. CTLA-4 blockade can also reduce T regulatory cell function, which may lead to an increase in anti-tumor immune response.

Treatment: Drugs: Nivolumab
A fully human immunoglobulin (Ig) G4 monoclonal antibody directed against the negative immunoregulatory human cell surface receptor programmed cell death-1 (PD-1,PCD-1) with immune checkpoint inhibitory and antineoplastic activities. Nivolumab binds to and blocks the activation of PD-1, an Ig superfamily transmembrane protein, by its ligands programmed cell death ligand 1 (PD-L1), overexpressed on certain cancer cells, and programmed cell death ligand 2 (PD-L2), which is primarily expressed on APCs (antigen presenting cells). This results in the activation of T-cells and cell-mediated immune responses against tumor cells or pathogens. Activated PD-1 negatively regulates T-cell activation and and plays a key role in in tumor evasion from host immunity.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Primary outcome [1] 0 0
To determine the clinical efficacy of the combination treatment of ipilimumab with nivolumab in rare cancers. - Clinical benefit rate for whole population (CR (complete response)+PR (partial response)+SD (stable disease)>3 months)
Timepoint [1] 0 0
at 12 weeks following randomisation then every 6 weeks until disease progression
Secondary outcome [1] 0 0
To identify whether a common predictive biomarker or immune signature can be identified in responding patients that can occur irrespective of tumour type. - Pre-dose Blood and Serum samples on Day 1 week 1 and Day 1 week 4 for cycle 1 and Day 1 week 1 for cycle 2 (each cycle is 6 weeks). Optional tumour biopsies will be assessed at Day 1 week 1 and Day 1 week 4 for both cycles 1 and 2.
Timepoint [1] 0 0
Pre-dose samples will be collected during the first two cycles (6 weeks/cycle)

Key inclusion criteria
1. Signed Written Informed Consent

- Subjects must be willing and able to comply with scheduled visits, treatment
schedule, laboratory testing, and other requirements of the study

2. Target Population

- Histologically confirmed Upper GI malignancies (Cholangiocarcinoma/ duodenal
carcinoma - collect MSI (microsatellite instability) status); Neuroendocrine
tumours (inc. pancreatic, bronchial and intestinal carcinoid tumours) and Rare
Gynaecological tumours (including but will not be limited to: vaginal or vulval
carcinomas, clear cell carcinoma of the ovary, low grade serous ovarian cancer,
mixed Mullarian tumours (carcinosarcoma), sarcomas of the female genital tract
and granulosa cell tumours).

- Eastern Cooperative Oncology Group (ECOG) performance status of 1

- Prior systemic therapy is permitted if it was completed at least 4 weeks prior to
enrolment, and all related adverse events have either returned to baseline or
stabilized or subjects are not suitable for, or if declining established standard

- Prior radiotherapy must have been completed at least 2 weeks prior to study drug

- Measurable disease by CT or MRI per RECIST 1.1 criteria

- Tumour tissue from an unresectable or metastatic site of disease must be provided
for biomarker analyses. If an insufficient amount of tumour tissue from an
unresectable or metastatic site is available prior to the start of the screening
phase, subjects must consent to allow the acquisition of additional tumour tissue
for performance of biomarker analyses.

- Screening laboratory values must meet the following criteria and should be
obtained within 14 days prior to randomization:

- WBC (white blood cells) > or = to 2000/µL

- Neutrophils > or = to 1500/µL

- Platelets > or = to 100 x103/µL

- Hemoglobin > 9.0 g/dL

- Serum creatinine < or = to 1.5 x ULN or creatinine clearance (CrCl) 40
mL/min (using the Cockcroft-Gault formula)

- AST/ALT (aspartate transaminase/alanine transaminase) < or = to 3 x ULN

- Total Bilirubin < or = to 1.5 x ULN (Upper limit of normal) (except subjects
with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL).

- Subject Re-enrolment: This study permits the re-enrolment of a subject that has
discontinued the study as a pre-treatment failure (i.e. subject has not been
treated) after obtaining agreement from the medical monitor prior to re enrolling
a subject. If re-enrolled, the subject must be re-consented.

3. Age and Reproductive Status

- Men and women, > or = to 18 years of age

- Women of childbearing potential (WOCBP) must use method(s) of contraception.
WOCBP should therefore use an adequate method to avoid pregnancy for 23 weeks (30
days plus the time required for Nivolumab to undergo five half lives) after the
last dose of investigational drug.

- Women must have a negative serum or urine pregnancy test (minimum sensitivity 25
IU/L or equivalent units of HCG) within 24 hours prior to the start of
investigational product.

- Women must not be breastfeeding

- Men who are sexually active with WOCBP must use any contraceptive method with a
failure rate of less than 1 percent per year. Men that are sexually active with
WOCBP must follow instructions for birth control when the half life of the
investigational drug is greater than 24 hours, contraception should be continued
for a period of 90 days plus the time required for the investigational drug to
undergo five half lives. The half life of nivolumab and ipilimumab is up to 25
days and 18 days, respectively. Given the blinded nature of the study, men who
are sexually active with WOCBP must continue contraception for 31 weeks (90 days
plus the time required for nivolumab to undergo five half lives) after the last
dose of investigational drug.

- Women who are not of childbearing potential (i.e. who are postmenopausal or
surgically sterile and azoospermic men do not require contraception.
Minimum age
18 Years
Maximum age
No limit
Both males and females
Can healthy volunteers participate?
Key exclusion criteria
1. Target Disease Exceptions

- Active brain metastases or leptomeningeal metastases. Subjects with brain
metastases are eligible if these have been treated and there is no magnetic
resonance imaging (MRI except where contraindicated in which CT scan is
acceptable) evidence of progression for at least 8 weeks after treatment is
complete and within 28 days prior to first dose of study drug administration.
Cases should be discussed with the medical monitor. There must also be no
requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day
prednisone equivalents) for at least 2 weeks prior to study drug administration.

2. Medical History and Concurrent Diseases

- Prior combination treatment directed against the PD-1/PDL1 (Programmed Death
Ligand 1) axis (anti PD 1, anti PD-L1, anti PD L2), and anti CTLA 4 antibody.
Prior monotherapy with these agents or other immune-stimulating/regulating agents
is permitted.

- Any serious or uncontrolled medical disorder that, in the opinion of the
investigator, may increase the risk associated with study participation or study
drug administration, impair the ability of the subject to receive protocol
therapy, or interfere with the interpretation of study results.

- Prior malignancy active within the previous 3 years except for locally curable
cancers that have been apparently cured, such as basal or squamous cell skin
cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix,
or breast.

- Subjects with active, known or suspected autoimmune disease. Subjects with
vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune
condition only requiring hormone replacement, psoriasis not requiring systemic
treatment, or conditions not expected to recur in the absence of an external
trigger are permitted to enroll.

- Subjects with a condition requiring systemic treatment with either
corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive
medications within 14 days of study drug administration. Inhaled or topical
steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are
permitted in the absence of active autoimmune disease.

3. Physical and Laboratory Test Findings

- Any positive test result for hepatitis B virus or hepatitis C virus indicating
acute or chronic infection

- Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS).

4. Allergies and Adverse Drug Reaction

- History of allergy to study drug components.

- History of severe hypersensitivity reaction to any monoclonal antibody.

5. Sex and Reproductive Status

- WOCBP who are pregnant or breastfeeding

- Women with a positive pregnancy test at enrolment or prior to administration of
study medication.

6. Other Exclusion Criteria

- Prisoners or subjects who are involuntarily incarcerated

- Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (e.g. infectious disease) illness.

Study design
Purpose of the study
Allocation to intervention
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?

Intervention assignment
Single group
Other design features
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Date of last participant enrolment
Date of last data collection
Sample size
Accrual to date
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Border Medical Oncology Unit - Albury
Recruitment hospital [2] 0 0
Blacktown Hospital - Sydney
Recruitment hospital [3] 0 0
Monash Health - Clayton
Recruitment hospital [4] 0 0
Austin Health - Heidelberg
Recruitment hospital [5] 0 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment postcode(s) [1] 0 0
2640 - Albury
Recruitment postcode(s) [2] 0 0
2145 - Sydney
Recruitment postcode(s) [3] 0 0
3168 - Clayton
Recruitment postcode(s) [4] 0 0
3078 - Heidelberg
Recruitment postcode(s) [5] 0 0
3000 - Melbourne

Funding & Sponsors
Primary sponsor type
Olivia Newton-John Cancer Research Institute
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Bristol-Myers Squibb
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Brief summary
The three tumour streams that will be studied in this protocol are: (i) upper GI malignancies
(comprising intra-hepatic/extra-hepatic cholangiocarcinomas,gall bladder cancers and duodenal
cancers).); (ii) neuroendocrine tumours (inc. Pancreatic, bronchial and intestinal carcinoid
tumours) and (iii) rare gynaecological tumours (including but will not be limited to: vaginal
or vulval carcinomas, clear cell carcinoma of the ovary, low grade serous ovarian cancer,
mixed mullarian tumours (carcinosarcoma), sarcomas of the female genital tract and granulosa
cell tumours).

The role of immunotherapy is being defined in more common cancer types, however because of
their rarity, the efficacy of immunotherapy for these cancers is poorly defined.

This protocol provides an important opportunity to establish whether the combination of
nivolumab & ipilimumab has efficacy in these cancers.
Trial website
Trial related presentations / publications
Public notes

Principal investigator
Name 0 0
Oliver Klein, MD
Address 0 0
ONJCRI and Austin Health
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications