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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04969887


Additional trial details provided through ANZCTR are available at the end of this record.


Registration number
NCT04969887
Ethics application status
Date submitted
6/07/2021
Date registered
21/07/2021
Date last updated
8/03/2024

Titles & IDs
Public title
Combination Immunotherapy in Rare Cancers Under InvesTigation
Scientific title
Ipilimumab and Nivolumab Combination Therapy in Patients With Selected Immunotherapy Sensitive Advanced Rare Cancers
Secondary ID [1] 0 0
CA209-6D6
Secondary ID [2] 0 0
ONJ2021-002
Universal Trial Number (UTN)
Trial acronym
MOST-CIRCUIT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced Biliary Tract Cancer 0 0
Neuroendocrine Tumors 0 0
Female Reproductive System Neoplasm 0 0
MSI-H Solid Malignant Tumor 0 0
Condition category
Condition code
Cancer 0 0 0 0
Neuroendocrine tumour (NET)
Cancer 0 0 0 0
Biliary tree (gall bladder and bile duct)
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)

Intervention/exposure
Study type
Interventional
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 480mg every 4 weeks until progression (up to 2 years)


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

Outcomes
Primary outcome [1] 0 0
Confirm the clinical efficacy of ipi/nivo in rare cancer histotypes which have demonstrated to be responsive to the regimen in the CA209-538 study.
Timepoint [1] 0 0
At 12 weeks following registration then as assessed by standard care until progression.
Primary outcome [2] 0 0
Determine the proportion of participants with progression free survival at 6 months
Timepoint [2] 0 0
Enrolment on study until 6 months.
Secondary outcome [1] 0 0
To confirm the overall survival of participants receiving ipi/nivo in rare cancer histotypes which have demonstrated to be responsive to the regimen
Timepoint [1] 0 0
From date of enrolment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years.
Secondary outcome [2] 0 0
To confirm the progression free survival of participants receiving ipi/nivo in rare cancer histotypes which have demonstrated to be responsive to the regimen
Timepoint [2] 0 0
From date of enrolment until the date of first documented progression up to 5 years.
Secondary outcome [3] 0 0
Quantification of treatment related toxicities to ipi/nivo according to CTCAE V5.0
Timepoint [3] 0 0
From 1st dose until 30 days following last dose [up to max 2 years + 30 days].

Eligibility
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

- a) Histologically confirmed Neuroendocrine cancers: Atypical bronchial carcinoid,
neuroendocrine carcinoma and Grade 3 NETs independent of primary site (SCLC
excluded); Biliary Tract Cancers: Intrahepatic cholangiocarcinoma, gallbladder
carcinoma; Gynaecological malignancies: Ovarian clear cell carcinoma, uterine
clear cell carcinoma, uterine/ovarian carcinosarcoma, uterine leiomyosarcoma,
vaginal/vulva squamous cell carcinoma; Mismatch repair protein deficient (MSI-H)
cancers (excluding colorectal carcinoma)

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

- Prior systemic therapy (=1) for advanced disease 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 participants are not suitable for, or if
declining established standard therapies. For MSI-H rare cancers and atypical
bronchial carcinoid only, patients will be eligible independent of the number of
prior lines of systemic treatment received as long as treatment has been
completed at least 4 weeks prior to enrolment.

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

- Measurable disease by CT or MRI per RECIST 1.1 criteria

- Tumour tissue from an unresectable or metastatic site of disease must be
available for 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 (in
the event of metastatic liver disease, an exception to this upper limit may
be accepted in consultation with the study physician).

- 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
Sex
Both males and females
Can healthy volunteers participate?
No
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
Treatment
Allocation to intervention
N/A
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
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
3/08/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/03/2028
Actual
Sample size
Target
Accrual to date
Final
240
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,VIC,WA
Recruitment hospital [1] 0 0
Border Medical Oncology Unit - Albury
Recruitment hospital [2] 0 0
Orange Health Service - Orange
Recruitment hospital [3] 0 0
Blacktown Hospital - Sydney
Recruitment hospital [4] 0 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [5] 0 0
Cairns and Hinterland Hospital and Health Service - Cairns
Recruitment hospital [6] 0 0
Townsville Hospital and Health Service - Douglas
Recruitment hospital [7] 0 0
Townville Hospital and Health Service - Townsville
Recruitment hospital [8] 0 0
Royal Adelaide Hospital - Adelaide
Recruitment hospital [9] 0 0
Royal Hobart Hospital - Hobart
Recruitment hospital [10] 0 0
Bendigo Health Services - Bendigo
Recruitment hospital [11] 0 0
Peninsula Health - Frankston
Recruitment hospital [12] 0 0
Barwon Health - Geelong
Recruitment hospital [13] 0 0
Austin Health - Heidelberg
Recruitment hospital [14] 0 0
Peter MacCalllum Cancer Centre - Parkville
Recruitment hospital [15] 0 0
Goulburn Valley Health - Shepparton
Recruitment hospital [16] 0 0
South West Healthcare - Warrnambool
Recruitment hospital [17] 0 0
Fiona Stanley Hospital - Perth
Recruitment postcode(s) [1] 0 0
2640 - Albury
Recruitment postcode(s) [2] 0 0
- Orange
Recruitment postcode(s) [3] 0 0
2145 - Sydney
Recruitment postcode(s) [4] 0 0
2298 - Waratah
Recruitment postcode(s) [5] 0 0
4870 - Cairns
Recruitment postcode(s) [6] 0 0
4814 - Douglas
Recruitment postcode(s) [7] 0 0
4814 - Townsville
Recruitment postcode(s) [8] 0 0
- Adelaide
Recruitment postcode(s) [9] 0 0
7000 - Hobart
Recruitment postcode(s) [10] 0 0
- Bendigo
Recruitment postcode(s) [11] 0 0
- Frankston
Recruitment postcode(s) [12] 0 0
- Geelong
Recruitment postcode(s) [13] 0 0
3084 - Heidelberg
Recruitment postcode(s) [14] 0 0
- Parkville
Recruitment postcode(s) [15] 0 0
3630 - Shepparton
Recruitment postcode(s) [16] 0 0
- Warrnambool
Recruitment postcode(s) [17] 0 0
- Perth
Recruitment outside Australia
Country [1] 0 0
New Zealand
State/province [1] 0 0
Auckland

Funding & Sponsors
Primary sponsor type
Other
Name
Olivia Newton-John Cancer Research Institute
Address
Country
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

Summary
Brief summary
The four tumour streams that will be studied in this protocol are based on immunotherapy
sensitive rare cancers from CA209-538 which will be further investigated under this protocol
and divided into four groups:

1. Neuroendocrine cancers: Atypical bronchial carcinoid, neuroendocrine carcinoma and Grade
3 NETs independent of primary site (SCLC excluded)

2. Biliary tract cancers: Intrahepatic cholangiocarcinoma and gallbladder carcinoma

3. Gynaecological malignancies: Ovarian clear cell carcinoma, uterine clear cell carcinoma,
uterine/ovarian carcinosarcoma, uterine leiomyosarcoma and vaginal/vulva squamous cell
carcinoma

4. Mismatch repair protein deficient (MSI-H) cancers (excluding colorectal carcinoma).

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
https://clinicaltrials.gov/ct2/show/NCT04969887
Trial related presentations / publications
Public notes

Contacts
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




Additional trial details provided through ANZCTR
Accrual to date
Recruiting in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 20
Blacktown Hospital
Recruitment postcode(s) [1] 25
2148
Funding & Sponsors
Funding source category [1] 49
Other
Name [1] 49
Minderoo Foundation
Address [1] 49
PO Box 3155, Broadway Nedlands, WA 6009
Country [1] 49
Australia
Primary sponsor
Charities/Societies/Foundations
Primary sponsor name
Olivia Newton-John Cancer Research Institute
Primary sponsor address
L5, ONJ Building
145 Studley Rd
Heidelberg, VIC 3084
Primary sponsor country
Australia
Ethics approval
Ethics application status
Approved
Ethics committee name [1] 25
Austin Health HREC
Address [1] 25
145 Studley Rd, Heidelberg, VIC 3084
Country [1] 25
Australia
Date submitted for ethics approval [1] 25
24/03/2021
Approval date [1] 25
28/05/2021
Ethics approval number [1] 25
HREC/73235/Austin-2021
 
Public notes

Contacts
Principal investigator
Title 245 0
Dr
Name 245 0
Oliver Klein
Address 245 0
Olivia Newton-John Cancer Research Institute L5 ONJ Building 145 Studley Rd Heidelberg, VIC, 3084
Country 245 0
Australia
Phone 245 0
Fax 245 0
Email 245 0
oliver.klein@onjcri.org.au
Contact person for public queries
Title 246 0
Dr
Name 246 0
Jodie Palmer
Address 246 0
L5, ONJCWC, Studley Rd
Country 246 0
Australia
Phone 246 0
04008902430394963573
Fax 246 0
Email 246 0
trials@onjcri.org.au
Contact person for scientific queries
Title 247 0
Dr
Name 247 0
Oliver Klein
Address 247 0
Olivia Newton-John Cancer Research Institute L5 ONJ Building 145 Studley Rd Heidelberg, VIC, 3084
Country 247 0
Australia
Phone 247 0
Fax 247 0
Email 247 0
oliver.klein@onjcri.org.au