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About
This clinical trial is evaluating the drug candidate TT-702 in patients with advanced solid tumours. The main aims of the trial are to determine the maximum dose of TT-702 that can be given safely to patients alone and in combination with other anti-cancer agents.
Full description
TT-702 is a 'small molecule prodrug'. TT-702 is converted into TT-478, which then targets and blocks the function of the 'A2B adenosine receptor'. It is hoped that by blocking this receptor the immune system will become more active in recognising and removing tumour cells.
This clinical trial has two phases:
The main aims of this trial are to:
Enrollment
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Inclusion criteria
Phase I, dose escalation phase
Histologically or cytologically proven advanced solid tumours refractory to conventional treatment, or for which no conventional therapy is considered appropriate by the Investigator or is declined by the patient. Phase I dose escalation cohorts are:
Phase II (expansion phase)
Histologically or cytologically proven advanced solid tumour of particular interest based on preclinical and clinical data, refractory to conventional treatment or, for which no conventional therapy is considered appropriate by the Investigator or, is declined by the patient. Phase II expansion cohorts are:
• Cohort 2M (TT-702 Monotherapy expansion cohorts) - mCRPC,TNBC and MMR/MSI defective tumours:
MMR/MSI defective tumours:
mCRPC:
TNBC:
Cohort 2A (TT-702 & darolutamide combination cohort): mCRPC.
Exclusion criteria
Radiotherapy (except single fractions for palliative reasons), endocrine therapy during the previous four weeks, immunotherapy and chemotherapy during the previous four weeks(previous six weeks for nitrosoureas, Mitomycin-C) before receiving TT-702. A washout period of eight weeks is required for enzalutamide and apalutamide before the patient receives their first dose of TT-702. A washout period of 4 weeks or 5 half-lives whichever is shorter for any other previous preceding IMPs is required before the patient receives their first dose of TT-702 (in the combination cohorts no washout is needed from PD-1/PD-L1 and darolutamide, respectively).
Patients with ongoing toxic manifestations of previous treatments greater than NCI CTCAE Version 5.0 Grade 1. Exceptions to this are alopecia and any ongoing toxic manifestation which in the opinion of the Investigator should not exclude the patient.
Patients with symptomatic brain or leptomeningeal metastases should be excluded. Asymptomatic patients with previously treated and stable brain metastases (in previous four weeks to study entry) and not requiring any steroids are eligible for the trial. Patients who are stable on anticonvulsants are also eligible.
Cohort 1M/2M (monotherapy) - Women of childbearing potential (or are already pregnant or lactating). However, those patients who meet the following points are considered eligible:
• Have a negative highly sensitive pregnancy test of a serum sample within 7 days prior to trial inclusion; and
• Agree to use two forms of medically approved contraception: i. one highly effective form including but not limited to: oral, injected,implanted, transdermal or intravaginal hormonal contraception associated with inhibition of ovulation; intrauterine device; intrauterine hormonereleasing system, bilateral tubal occlusion or vasectomised partner; ii. plus a barrier method (for example, condom plus spermicide); iii. or agree to sexual abstinence. Effective from the first administration of TT-702, throughout the trial and for six months after the last administration of IMP.
Male patients with partners of childbearing potential. However, those patients who meet the following points are considered eligible:
Major thoracic or abdominal surgery from which the patient has not yet recovered.
At high medical risk because of non-malignant systemic disease including active uncontrolled infection. Patients with previous Hepatitis C exposure but no current infection are eligible to participate.
Known to be serologically positive for Hepatitis B, Hepatitis C or Human Immunodeficiency Virus (HIV).
Prior bone marrow transplant or have had extensive radiotherapy to greater than 25% of bone marrow within eight weeks.
Concurrent congestive heart failure, prior history of class II-IV cardiac disease (New York Heart Association [NYHA]), prior history of clinically significant cardiac ischaemia or prior history of clinically significant cardiac arrhythmia. Patients with significant cardiovascular disease are excluded as defined by:
Is a participant or plans to participate in another interventional clinical trial, whilst taking part in this Phase I/II trial of TT-702. Participation in an observational trial or interventional clinical trial which does not involve administration of an IMP and which would not place an unacceptable burden on the patient in the opinion of the Investigator would be acceptable.
Previous malignancies of other types, apart from adequately treated in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for five years or more and are deemed at negligible risk for recurrence, are eligible for the trial.
A concomitant significant other illness that might in the opinion of the Investigator affect compliance with the protocol or interpretation of results, examples include but are not limited to autoimmune diseases or immune deficiency, or other disease with ongoing fibrosis (such as scleroderma, pulmonary fibrosis, emphysema, neurofibromatosis, palmar/plantar fibromatosis), alcoholic hepatitis, cirrhosis, and inherited liver disease, previous organ transplantation, uncontrolled or poorly controlled diabetes mellitus (for example HbA1c >10%) and patients with non-alcoholic steatohepatitis.
History of an immune-mediated adverse event of Grade 3 or above attributed to prior cancer immunotherapy that resulted in permanent discontinuation of the prior immunotherapeutic agent. Immune-mediated adverse events related to prior immunomodulatory therapy (other than endocrinopathy managed with replacement therapy or stable vitiligo) that have not either resolved completely to baseline or are Grade ≤2 in severity.
Patients on systemic corticosteroids (apart from replacement doses for endocrinopathy up to an equivalent of 10 mg QD prednisolone). Topical or inhaled steroids for pre-existent diseases are allowed.
Patients who received a live vaccine within 30 days before trial enrolment are excluded.
Patients with a known or suspected history of hypersensitivity or allergy to TT-702, or any of its excipients (for any strength) are excluded:
Cohort 1A/2A (TT-702 & darolutamide) - Patients with a known or suspected history of hypersensitivity or allergy to darolutamide or any of its excipients: calcium hydrogen phosphate, croscarmellose sodium, lactose monohydrate, magnesium stearate, povidone, hypromellose, lactose monohydrate, macrogol, and titanium dioxide.
Patients who take therapies that inhibit or induce CYP3A must be excluded.
Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.
If a patient is taking any dietary supplements or complementary medicines/botanicals, the Sponsor's Centre for Drug Development (CDD) must be informed at the earliest opportunity both prior to enrolment and during the patient's time on trial.
Primary purpose
Allocation
Interventional model
Masking
188 participants in 6 patient groups
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Central trial contact
Johann de Bono, Prof
Data sourced from clinicaltrials.gov
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