Clinical Trial Details

Combination Immunotherapy in Rare Cancers Under InvesTigation

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Trial Information

Broad Health Condition Advanced Biliary Tract Cancer
Neuroendocrine Tumors
Female Reproductive System Neoplasm
MSI-H Solid Malignant Tumor

Specific Health Condition

Trial FocusTreatment

Recruitment statusRecruiting

Recruitment Details
Recruitment State

Blacktown Hospital

Phase of TrialPhase 2

Trial 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

  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.

Key inclusion criteria

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

         -  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.

  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.

Minimum age18 Years


Can Healthy volunteers participate?No

Contact details and further information

Sponsor Primary Sponsor Type: Other
Primary Sponsor Name: Olivia Newton-John Cancer Research Institute

Trial website

Trial IDNCT04969887