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Trial registered on ANZCTR


Registration number
ACTRN12617001059358
Ethics application status
Approved
Date submitted
17/07/2017
Date registered
20/07/2017
Date last updated
12/04/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
IPINIVO - A Pharmacodynamics study of Nivolumab in Combination with Ipilimumab in Patients with Advanced or Metastatic Solid Tumours'
Scientific title
A Phase II, Multicenter, Open Label Study to Evaluate the Pharmacodynamics of Nivolumab in Combination with Ipilimumab in Subjects with Advanced or Metastatic Solid Tumors
Secondary ID [1] 292153 0
None
Universal Trial Number (UTN)
Trial acronym
IPINIVO
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced or Metastatic Solid Tumours 303594 0
Condition category
Condition code
Cancer 303004 303004 0 0
Malignant melanoma
Cancer 303396 303396 0 0
Lung - Non small cell
Cancer 303397 303397 0 0
Hodgkin's
Cancer 303398 303398 0 0
Kidney
Cancer 303399 303399 0 0
Head and neck
Cancer 303402 303402 0 0
Bladder
Cancer 303404 303404 0 0
Prostate
Cancer 303405 303405 0 0
Bowel - Back passage (rectum) or large bowel (colon)
Cancer 303406 303406 0 0
Brain
Cancer 303421 303421 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Approximately 21 eligible patients with advanced or metastatic solid tumors will be enrolled into two cohorts.
In the first cohort, nine (9) subjects will receive 1mg/kg of ipilimumab every 6 weeks and Nivolumab 3mg/kg every 2 weeks until disease progression or discontinuation due to toxicity or a maximum of 12 weeks.
The second cohort of twelve (12) subjects will receive 0.3mg/kg of ipilimumab every 6 weeks and Nivolumab 3mg/kg dosed every 2 weeks until disease progression or discontinuation due to toxicity or a maximum of 12 weeks.
Chort 1 and Cohort 2 will not be enrolled concurrently. Cohort 2 shall proceed after review of all Cohort 1 Day 8 data to identify if the study end point has been met.
Nivolumab & Ipilimumab are administered intravenously in clinic at the study sites under the review of study doctors and nurses to ensure this is correctly administered and to review for any adverse reaction. When administered in combination Nivolumab is infused first followed by Ipilimumab on the same day.
Intervention code [1] 298300 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 302377 0
To evaluate the change in Ki-67 expression in CD4+ peripheral blood T-cells as a pharmacodynamic biomarker for the effect of nivolumab in combination with ipilimumab on peripheral T-cells.
Timepoint [1] 302377 0
Change in Ki-67 expression from baseline in CD4+ peripheral blood T-cells at Cycle 1, Day 4 and Day 8 and from baseline to the end of the first 6-week cycle.
Secondary outcome [1] 335774 0
To evaluate the change in immune cell subsets in peripheral blood T-cells as pharmacodynamic biomarkers for the effect of nivolumab in combination with ipilimumab.
Timepoint [1] 335774 0
Change in peripheral blood immune cell profiles from baseline to end of 6-week cycle and end of second cycle treatment, week 12.
Secondary outcome [2] 335775 0
To evaluate the change in mRNA expression in peripheral blood T-cells as pharmacodynamic biomarkers for the effect of nivolumab in combination with ipilimumab on peripheral T-cells.
Timepoint [2] 335775 0
Change in mRNA expression in peripheral blood T-cells from baseline during the first 6-week cycle and from the start of the second 6-week cycle, week 7, to the end of the second cycle treatment, week 12..
Secondary outcome [3] 335776 0
Evaluate best overall response (BOR) per RECIST 1.1.
Timepoint [3] 335776 0
End of Treatment is defined as 12 weeks after the last participant received first dose of nivolumab and ipilimumab or 2 weeks after the last participant receives their last dose of either drug.
Secondary outcome [4] 336998 0
Safety will be evaluated through physical examinations, vital signs, clinical laboratory tests, ECG, ECOG performance status and adverse events.
Timepoint [4] 336998 0
Safety will be evaluated for the duration of study participation, from baseline until end of treatment, defined as end of week 12 or 2 weeks post final dose of study drug.

Eligibility
Key inclusion criteria
1. Willing and able to give signed written informed consent.
2. Male or female subjects aged > 18 years.
3. Subjects must have a histologically or cytologically confirmed, metastatic or locally advanced solid tumor for which no standard therapy exists or standard therapy has failed.
4. Performance status score 0-1 (Eastern Cooperative Oncology Group Scale)
5. Estimated life expectancy > 3 months.
6. Subjects must have pretreatment clinical laboratory values meeting the following criteria during the Screening Phase (subjects may be retested during Screening Phase):
• Adequate hematological function defined by white blood cell count (WBC) > 3 x 109/L, absolute neutrophil count (ANC) > 1.5 x 109/L, lymphocyte count > 0.5 x 109/L, platelet count > 100 x 109/L, and hemoglobin > 9 g/dL (may be transfused). For subjects with gastric cancer only, acceptable parameters for WBC, ANC, and lymphocytes are as follows: WBC > 2 x 109/L, ANC > 1.0 x 109/L, and lymphocyte count > 0.5 x 109/L.
• Adequate hepatic function based by a total bilirubin level < 1.5 x the institutional upper limit of normal (IULN), and aspartate aminotransferase (AST) level < 2.5 x IULN, and an alanine aminotransferase (ALT) level < 2.5 x IULN. For subjects with documented metastatic disease to the liver, AST and ALT levels < 5 x IULN.
• Adequate renal function defined by an estimated clearance > 50 mL/min according to Cockcroft-Gault formula or measured 24-hour creatinine clearance (or local institutional standard method).
7. Effective contraception for both male and female subjects if risk of conception exists.
Note: Nivolumab and ipilimumab can cause fetal harm. Thus, women of childbearing potential and men must agree to use effective contraception, defined as 2 barrier methods, or 1 barrier method with an intrauterine device or use of oral female contraceptive. Subjects must confirm use of effective contraception at least 28 days before first study drug administration and for the duration of trial participation. Female subjects will be advised to maintain effective contraception for at least 5 months after the last treatment dose. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this trial, the treating physician should be informed immediately.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Prior therapy with any antibody/drug targeting T cell co-regulatory proteins (immune checkpoints), such as anti-PD-1, anti-PD-L1, or anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody.
2. Concurrent anticancer treatment (e.g., cytoreductive therapy, radiotherapy except for palliative bone-directed radiotherapy, immune therapy, or cytokine therapy except for erythropoietin) within 21 days or 5x (five times) their half-lives (whichever is shorter) before the first dose of trial treatment; major surgery within 28 days before start of trial treatment (excluding prior diagnostic biopsy); or use of hormonal agents within 7 days before start of trial treatment, except for subjects with castration-resistant prostate cancer (CRPC), who may remain on treatment with luteinizing hormone–releasing hormone agonists or antagonists.
Note: Subjects receiving bisphosphonate or denosumab are eligible provided that treatment was initiated equal to 14 days before first dose of treatment.
3. Use of any investigational drug within 21 days or 5x their half-lives (whichever is shorter) before the first dose of trial treatment.
4. Subjects receiving immunosuppressive agents (such as steroids) for any reason should be tapered off these drugs 14 days before initiation of trial treatment. Steroids with no or minimal systemic effect (topical, inhalation) are allowed.
Note: Use of inhaled or topical corticosteroid is permitted.
Note: Steroid pre-medication for radiographic imaging for dye allergies is permitted.
5. Rapidly progressive disease.
6. Active central nervous system metastases.
7. Receipt of any organ transplantation, including allogeneic stem-cell transplantation.
8. Significant acute or chronic infections, including:
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
• Positive test for hepatitis B virus (HBV) surface antigen and/or confirmatory hepatitis C virus (HCV) RNA (if anti-HCV antibody tested positive).
9. Active or history of any autoimmune disease (subjects with diabetes type 1, vitiligo, psoriasis, hypo-, or hyperthyroid disease not requiring immunosuppressive treatment are eligible) or immunodeficiencies.
10. Known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE grade equal to 3), any history of anaphylaxis, or uncontrolled asthma (i.e., equal to 3 features of partly controlled asthma).
11. Persisting toxicity related to prior therapy of NCI CTCAE grade greater than 1 severity. Sensory neuropathy of grade 2 is acceptable.
12. Pregnancy or breast feeding.
13. Known alcohol or drug abuse.
14. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (less than 6 months before enrollment), myocardial infarction (less than 6 months before enrollment), unstable angina, congestive heart failure (New York Heart Association class is equal to II), or serious uncontrolled cardiac arrhythmia requiring medication.
15. All other significant diseases (e.g., inflammatory bowel disease) that, in the opinion of the investigator, might impair the subject’s tolerance of trial treatment.
16. Any psychiatric condition that would prohibit understanding or rendering of informed consent.
17. Legal incapacity or limited legal capacity.
18. Vaccination within 4 weeks of first dose of the combination nivolumab/ipilimumab and while on study except for administration of inactivated vaccines (e.g., inactivated influenza vaccines).

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
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
Other design features
Phase
Phase 2
Type of endpoint(s)
Pharmacodynamics
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD

Funding & Sponsors
Funding source category [1] 296688 0
Commercial sector/Industry
Name [1] 296688 0
Agenus Inc
Address [1] 296688 0
3 Forbes Road, Lexington, MA, 02421
Country [1] 296688 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Clinical Network Services
Address
Level 4, 88 Jephson Street, Toowong QLD 4066
Country
Australia
Secondary sponsor category [1] 295650 0
None
Name [1] 295650 0
None
Address [1] 295650 0
Country [1] 295650 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297913 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 297913 0
129 Glen Osmond Road Eastwood South Australia 5063
Ethics committee country [1] 297913 0
Australia
Date submitted for ethics approval [1] 297913 0
17/05/2017
Approval date [1] 297913 0
26/06/2017
Ethics approval number [1] 297913 0

Summary
Brief summary
This study aims to evaluate the effects of Nivolumab in Combination with Ipilimumab on biochemical and physiologic functions in Subjects with Advanced or Metastatic Solid Tumors.

Who is it for?
You may be eligible to join this study if you are aged 18 years or above and have a histologically or cytologically confirmed, metastatic or locally advanced solid tumor for which no standard therapy exists or standard therapy has failed.

Study details
Approximately 21 eligible patients with advanced or metastatic solid tumors will be enrolled into two cohorts.
In the first cohort, nine (9) subjects will receive 1mg/kg of ipilimumab every 6 weeks and Nivolumab 3mg/kg every 2 weeks until disease progression or discontinuation due to toxicity or a maximum of 12 weeks.
The second cohort of twelve (12) subjects will receive 0.3mg/kg of ipilimumab every 6 weeks and Nivolumab 3mg/kg dosed every 2 weeks until disease progression or discontinuation due to toxicity or a maximum of 12 weeks.

The investigators seek to identify/confirm circulating pharmacodynamic biomarkers that correlate with immune activation.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 75446 0
Prof Paul De Souza
Address 75446 0
Southside Cancer Care Centre
Level 3, 533 Kingsway
MIRANDA NSW 2228
Country 75446 0
Australia
Phone 75446 0
+61 2 85569350
Fax 75446 0
Email 75446 0
P.DeSouza@westernsydney.edu.au
Contact person for public queries
Name 75447 0
Prof Paul De Souza
Address 75447 0
Southside Cancer Care Centre
Level 3, 533 Kingsway
MIRANDA NSW 2228
Country 75447 0
Australia
Phone 75447 0
+61 2 85569350
Fax 75447 0
Email 75447 0
P.DeSouza@westernsydney.edu.au
Contact person for scientific queries
Name 75448 0
Prof Paul De Souza
Address 75448 0
Southside Cancer Care Centre
Level 3, 533 Kingsway
MIRANDA NSW 2228
Country 75448 0
Australia
Phone 75448 0
+61 2 85569350
Fax 75448 0
Email 75448 0
P.DeSouza@westernsydney.edu.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary