CompletedPhase 2ACTRN12620000984998

Cancer Molecular Screening and Therapeutics (MoST) Program Substudy Addendum 11 substudy 25-26: Tildrakizumab

Single arm, open label signal seeking, phase II trial to study the clinical activity of Tildrakizumab in patients with advanced osteosarcoma and soft tissue sarcomas

Sponsor

The University of Sydney

Enrollment

32 participants

Start Date

Mar 9, 2021

Study Type

Interventional

Conditions

Soft Tissue Sarcoma Cancer Advanced Osteosarcoma

Summary

This is a substudy of the Cancer Molecular Screening and Therapeutics (MoST) Program, which is registered on ANZCTR with ID ACTRN12616000908437. This substudy will evaluate the activity of Tildrakizumab in patients 18 years or older, with pathologically confirmed advanced osteosarcoma or soft-tissue sarcomas. Who is it for: You may be eligible to join the study if you are aged 18 years and older, with pathologically confirmed advanced and/or metastatic cancer of any histologic type, including haematological cancers, or an earlier diagnosis of a poor prognosis cancer and have confirmed molecular markers. Molecular profiling will be performed and assessed by the Molecular Tumour Board who will confirm if you have the right molecular markers for this study . Study details: Eligible participants will receive Tildrakizumab at a dose of 200mg every 28 days continuously via subcutaneous injection as long as they and their doctor agree there is a benefit from treatment. Tildrakizumab works by targeting a protein called IL-23, and recent research conducted at Garvan Institute has shown that IL-23 may be involved in growth of sarcomas and osteosarcomas. Tildrakizumab is approved in Australia and is used to treat psoriasis. However, tildrakizumab is not approved to treat bone or soft tissue sarcoma and is therefore an investigational treatment for these advanced and rare cancer types. Clinical and safety assessments are scheduled prior to registration and then every 4 weeks during treatment. Clinical assessments will continue until treatment is stopped. We cannot guarantee that patients will receive any benefits from this study. This study is being carried out to improve the way we treat cancer patients who may have limited treatment options available to them. It is hoped that Tildrakizumab will be well tolerated and will improve outcomes for future patients, however, there may be no clear benefit from participation in this study.

Eligibility

Sex: Both males and femalesMin Age: 18 Yearss

Inclusion Criteria39

Male or female patients, aged 18 years and older, with pathologically confirmed advanced and/or metastatic cancer of any histologic type, including haematological cancers, or an earlier diagnosis of a poor prognosis cancer;
Sufficient and accessible tissue for molecular screening;
Patients receiving their last line of standard treatment or who have received and failed all standard anticancer therapy (where standard therapy exists) or have documented unsuitability for any further standard anticancer therapy. Poor prognosis cancers or cancers with low expected response rate to standard treatment (in the opinion of the investigator and based on available evidence) may be screened on an earlier line of treatment.
a. Failure is defined as either progression of disease (clinical or radiological) or intolerance to standard therapy resulting in the discontinuation of the therapy.
b. Documented unsuitability for further standard therapy includes known hypersensitivity, organ dysfunction or other patient factors that would make therapy unsuitable in the judgement of the responsible investigator;
Eastern Cooperative Oncology Group (ECOG) Performance Status performance status 0, 1 or 2;
Willing and potentially able to comply with study requirements, including treatment, timing and/or nature of required assessments; It is the intention to screen patients who are in principle wishing to take part in a MoST substudy if they are found to have an appropriate tumour biomarker and are still eligible for enrolment at the time of the treatment phase;
It is the intention to screen patients who are in principle wishing to take part in a MoST substudy if they are found to have an appropriate tumour biomarker and are still eligible for enrolment at the time of the treatment phase (substudy).
Adults, aged 18 years and older, with pathologically confirmed advanced osteosarcoma or soft-tissue sarcoma;
Has measurable disease as defined by RECIST 1.1;
Confirmation of molecular eligibility by the molecular tumour board;
ECOG 0-2;
Sufficient and accessible tumour tissue for exploratory objectives
Received and failed all standard anticancer therapy or have documented unsuitability for any further standard therapy, if standard therapy exists;
Clinical or radiological progression on or following last anticancer therapy unless such anticancer therapy stopped due to toxicity / treatment intolerance;
Adequate organ system function as assessed by the following minimal laboratory requirements (within 7 days prior to first administration of study drug):
a. bone marrow function; platelets greater than or equal to 100 x 109/L, ANC greater than or equal to 1.5 x 109/L, and haemoglobin greater than or equal to 9g/dL (5.6mmol/L);
b. liver function; ALT/AST less than or equal to 3 x ULN (in the absence of liver metastases, less than or equal to 5 x ULN for patients with liver involvement)
and total bilirubin less than or equal to 1.5xULN;
c. renal function; serum creatinine less than or equal to 1.5xULN;
Archival tissue sample available
Willing and able to comply with all study requirements, including treatment, timing, and on-treatment biopsy.
Signed, written informed consent to participation in the specific treatment substudy.
The patient is considered to be eligible according to the following tuberculosis (TB) screening criteria, defined as:
a. No history of untreated latent or active TB prior to screening.
b. Has no signs or symptoms suggestive of active TB upon medical history and/or physical examination.
c. Has had no recent close contact with a person with active TB OR, if there has been such contact, to be referred to a respiratory physician at least 4 weeks prior to the first administration of study medication.
d. Has a negative diagnostic TB test results, defined as a negative intradermal tuberculin skin test (TST) or a negative QuantiFERON-TB Gold test (QFTG) within 4 weeks prior to first administration of study medication.
e. A subject who has a positive contact history, or a positive TST or QFTG test, or has signs or symptoms suggestive of active TB upon medical history and physical examination, must have a negative chest X-ray (both posterior-anterior and lateral views) or chest computed tomography (CT) scan taken within 4 weeks prior to first administration of study medication to exclude current active TB or old inactive TB, read by a qualified radiologist.
f. Patient with LTBI, defined as a positive TST and QFTG but no clinical and radiological evidence of active TB infection, may be included if they receive prophylactic treatment, or have previously completed an adequate course of prophylactic treatment according to local guidelines or regulations without subsequent new exposure to active TB. Prophylactic treatment for LTBI must be initiated at least 4 weeks prior to first administration of study medication, as per local guidelines.
g. Referral to a respiratory specialist physician is strongly encouraged to assess the need for repeat of prophylactic therapy if there is a history of new exposure to active TB subsequent to completion of prior treatment for LTBI or if prior treatment of LTBI was completed more than 3 months prior to screening.
Female subject must be:
a. Postmenopausal status as determined by:
i. greater than or equal to 45 years of age with more than 1 year since last menses, more than or equal to 2 years after completion of last dose cytotoxic chemotherapy, OR
ii. If a subject is less than 45 years of age, follicle-stimulating hormone (FSH) level must be documented as elevated into the postmenopausal range at screening.
b. Pre-menopausal female and agrees to abstain from heterosexual activity, OR use a medically accepted and appropriate effective method of contraception.
Patient must have negative human immunodeficiency virus (HIV) test result, hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) test results.
For women of childbearing potential, a negative serum pregnancy test at screening and a negative urine pregnancy test within 24 hours prior to the first dose of study medication.
Patient must have a satisfactory physical examination within normal limits or clinically acceptable limits to the investigator prior to the first dose of study medication.

Exclusion Criteria34

Exclusions criteria - molecular screening
Suitable for standard therapy or accepted standard care, if the patient has not been previously treated;
Specific comorbidities or conditions (e.g. psychiatric) or concomitant medications which may contraindicate participation and/or interact with the investigational product;
Other co-morbidities or conditions that may compromise assessment of key outcomes or in the opinion of the clinician, limit the ability of the patient to comply with the protocol;
For non central nervous system (CNS) cancers, patients with symptomatic CNS involvement of his/her cancer are excluded. Subjects with stable neurological function on stable doses of steroids/anti-epileptics over 4 weeks, and with no evidence of CNS progression within 12 weeks prior to screening are eligible;
History of another malignancy within 2 years prior to molecular screening registration are excluded unless adequately treated and determined free of progressive and metastatic disease for at least 6 months. Patients with a past history of adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or superficial transitional cell carcinoma of the bladder can be included;
Pregnancy, lactation or inadequate contraception.
Contraindications to investigational product;
Known history of hypersensitivity to active or inactive components of investigational product or latex;
Previous treatment with tildrakizumab (MK-3222) or other IL-23/Th-17 pathway inhibitors, including p40, p19, and IL-17 antagonists.
Specific co-morbidities or conditions (e.g. psychiatric) or concomitant medications which may interact with the investigational product(s);
Presence of any infection or history of recurrent infection requiring treatment with systemic antibiotics within 2 weeks prior to screening, or severe infection (e.g., pneumonia, cellulitis, bone, or joint infections) requiring hospitalization or treatment with intravenous antibiotics within 8 weeks prior to screening.
Co-morbidities or conditions that may compromise assessment of key outcomes or in the opinion of the clinician, limit the ability of the patient to comply with the protocol;
Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment:
a. Radiation therapy, surgery or tumour embolization within 14 days prior to the first dose of study treatment. Palliative radiotherapy (for analgesia) is acceptable only if the irradiated field does not include target lesions;
b. Immunotherapy within 28 days prior to the first dose of study treatment;
c. Chemotherapy, biologic therapy, or hormonal therapy within 14 days or 5 half-lives of a drug prior to the first dose of study treatment or until recovery from previous therapy (whichever is longer);
Any unresolved toxicity ( greater than CTCAE grade 2) from previous anti-cancer therapy. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripheral neuropathy);
Any significant organ dysfunction or clinically significant laboratory abnormalities that place the subject at unacceptable risk for participation in a trial of an immunomodulatory therapy in the judgment of the investigator, within 6 months prior to screening.
Hospitalization due to an acute cardiovascular event, cardiovascular illness, or cardiovascular surgery within 6 months of screening.
Uncontrolled hypertension (systolic blood pressure of greater than or equal to 160 mm Hg and/or diastolic blood pressure of greater than or equal to 100 mm Hg at screening) or uncontrolled diabetes at screening
Administration of any investigational treatment within the indicated washout period prior to receiving the first dose of study treatment:
a. Live viral or bacterial vaccination within 28 days.
b. Injectable or oral corticosteroids (greater or equal to daily dose of 20 mg equivalent of prednisone) within 28 days
c. Received another biological agent (e.g., monoclonal antibodies), including immune checkpoint blockades, within 28 days
d. Concurrent participation in an interventional trial with another pharmacologic agent (Observational studies are permitted).
e. Participated in an interventional clinical trial within 4 weeks or 5 half-lives of a drug (whichever is longer)
f. Radiation therapy, surgery or tumour embolization within 14 days. Palliative radiotherapy (for analgesia) is acceptable only if the irradiated field does not include target lesions
g. Chemotherapy, biologic therapy, or hormonal anticancer therapy within 14 days or 5 half-lives of a drug or until recovery from previous therapy (whichever is longer)
Symptomatic CNS metastasis or leptomeningeal disease from underlying sarcoma, unless the participant has a stable neurological function, on stable doses of steroids/anti-epileptics over 4 weeks, and with no evidence of CNS progression within 12 weeks prior to screening;
Concurrent or a past history of another malignancy prior to molecular screening with a less favourable prognosis than the index malignancy are permitted to participate, except for:
a. adequately treated skin cancers (including basal cell carcinoma, squamous cell carcinoma squamous cell carcinoma), superficial transitional cell carcinoma of the bladder, or carcinoma of cervix uteri, or;
b. other solid or haematological malignancies determined to be free of progressive and metastatic disease at the time of screening.
Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration. Men must have been surgically sterilised or use a (double if required) barrier method of contraception

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Interventions

Tildrakizumab is the study intervention in this trial and is registered with the TGA for plaque psoriasis. Tildrakizumab will be administered by the Study Coordinator/Research Nurse via subcutan

Tildrakizumab is the study intervention in this trial and is registered with the TGA for plaque psoriasis. Tildrakizumab will be administered by the Study Coordinator/Research Nurse via subcutaneous injection as a flat dose of 200 mg every 4 weeks and will be administered continuously until disease progression is documented or when the participant experiences intolerable toxicity or withdraws for another reason. No dose reductions will be allowed. Participant medication compliance will be determined at each clinic visit by standard compliance assessments to determine the actual dose taken. Participants will be asked to return unused drug and empty drug containers at each return visit. The Pharmacy Department at participating institutions will maintain a record of drugs dispensed for each participant.