TT-702 in Patients With Advanced Solid Tumours.

Study Overview
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Brief Summary
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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.

Detailed Description
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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: Phase I, dose escalation phase - groups of patients will receive increasing doses of TT-702 to find an optimal dose that best targets the tumours. This phase will consist of both monotherapy and combination escalation cohorts. The combination agents to be used with TT-702 have not yet been defined. Phase II, expansion phase - larger groups of patients will receive the selected dose of TT-702 considered to be optimal in the Phase I, dose escalation phase. This phase will consist of three monotherapy expansion cohorts (metastatic castrate resistant prostate cancer [mCRPC] cohort, Mismatch Repair [MMR]/ Microsatellite Instability [MSI] defective tumours cohort and a triple negative breast cancer [TNBC] cohort) and combination expansion cohorts. The combination agent to be used with TT-702 has not yet been defined. The main aims of this trial are to: Find the maximum dose of TT-702 as a monotherapy and in combination with other anti-cancer drugs that can be given safely to patients. Define the side effects of TT-702 and how these can be managed. Determine the pharmacokinetics (PK) and elimination kinetics of TT-702.

Official Title
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CURATE - A Cancer Research UK Phase I/II, Dose Escalation and Expansion Trial of TT-702, A Selective Adenosine A2BR Antagonist, Given Orally as a Monotherapy Agent and in Combination, in Patients With Advanced Solid Tumours

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: TT-702


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Be able to provide informed consent and be capable of co-operating with IMP administration, procedures and follow-up. Be willing to provide samples (blood and tissue) as required. Consent to access any available archival tissue. Consent for fresh tumour biopsy samples at baseline and on trial (optional for patients in the dose escalation phase, mandatory for a minimum of eight patients in each expansion cohort). Life expectancy estimated by the Investigator to be at least 12-weeks. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Aged 16 years or over at the time consent is given. Haematological and biochemical indices within the protocol specified ranges. Has radiological disease progression (and/or, in mCRPC patients, PSA progression according to PCWG3 criteria) at the time of study enrolment. Castrate levels of testosterone (<1.7 nmol/L (50 ng/dL) (mCRPC patients only). Phase I, dose escalation phase • Phase I, Cohort 1M (TT-702 monotherapy cohort): Any solid tumour for which standard of care has been exhausted or, is considered inappropriate for or, declined by the patient. Phase II (expansion phase) - mCRPC mCRPC patients must have progressive disease according to PCWG3 criteria Prior treatment with a next generation hormonal agent Adenocarcinoma without predominant neuroendocrine or small cell features Phase II (expansion phase) - TNBC Patients must have at least one measurable lesion according to RECIST criteria Version 1.1, that has had objective radiological progression on or after the last therapy. Human epidermal growth factor receptor 2 negativity (negative IHC staining [score 0 or 1] or negative fluorescence in situ hybridization based on the American Society of Clinical Oncology/College of American Pathologists guidelines and recommendations) and determined through local testing in NHS lab within UKAS/ISO15198 scope of accreditation Note: patients initially diagnosed with hormone receptor-positive and/or HER2-positive breast cancer OR de novo metastatic patients with a primary tumour hormone receptor-positive (weak positivity or ER negativity and progesterone receptor positivity) considered as non-clinically relevant are eligible if the tumour biopsy obtained from a local recurrence or distant metastasis site confirms the TNBC disease. Estrogen receptor and progesterone receptor negativity (< 1% positive staining cells in the invasive tumour) determined locally using IHC per American Society of Clinical Oncology/College of American Pathologists criteria. Phase II (expansion phase) - MMR/MSI defective tumours Patients must have at least one measurable lesion according to RECIST criteria Version 1.1, that has had objective radiological progression on or after the last therapy. Prior treatment with an anti-programmed death 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) agent, either as monotherapy or in combination with other agent(s). This should be the preceding treatment prior to trial entry. Diagnosis of metastatic MSI-H (defined as MSI polymerase chain reaction test with instability shown in ≥ 2 or ≥ 30% of microsatellite markers) or metastatic dMMR (defined as loss of MLH1, MSH2, MSH6, and/or PMS2 expression is detected) through local testing in NHS lab within UKAS/ISO15198 scope of accreditation. 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 4 weeks or 5 half-lives whichever is shorter of any other previous preceding investigational medicinal products (IMP) 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 androgen axis/androgen receptor antagonists respectively, these agents are yet to be defined). Patients with ongoing toxic manifestations of previous treatments greater than NCI-CTCAE V5.0 Grade 1. Exceptions to this are alopecia and any ongoing toxic manifestation which in the opinion of the Investigator and the Medical Advisor 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. Women of childbearing potential (or are already pregnant or lactating) unless willing to adhere to protocol-defined contraceptive requirements. Male patients with partners of childbearing potential unless willing to adhere to protocol-defined contraceptive requirements. 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), prior history of clinically significant cardiac ischaemia , prior history of clinically significant cardiac arrhythmia or other clinically significant cardiovascular disease as defined by the trial protocol. 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 and Medical Advisor 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 haemoglobin A1c [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 prednisolone once daily). 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, its excipients (hydroxypropyl cellulose, sodium lauryl sulfate, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium and magnesium stearate), or TT-478 (also known as GS-6201 or CVT-6883) are excluded. 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.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1M (Monotherapy dose escalation cohort)<br>This cohort will recruit patients with solid tumours. | Drug: TT-702<br>* TT-702 will be administered orally, once daily, for up to 12 months.<br>|
| Experimental: Cohort 2M: mCRPC (Monotherapy expansion cohort)<br>This cohort will recruit patients with mCRPC only. | Drug: TT-702<br>* TT-702 will be administered orally, once daily, for up to 12 months.<br>|
| Experimental: Cohort 2M: MSI/MMR defective tumours (Monotherapy expansion cohort)<br>This cohort will recruit patients with MSI/MMR defective tumours only. | Drug: TT-702<br>* TT-702 will be administered orally, once daily, for up to 12 months.<br>|
| Experimental: Cohort 2M: TNBC (Monotherapy expansion cohort)<br>This cohort will recruit patients with TNBC only. | Drug: TT-702<br>* TT-702 will be administered orally, once daily, for up to 12 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) (Dose Escalation Phase) | Determine a dose that is deemed tolerable with a target dose limiting toxicity (DLT). | Day 1 to Day 21 | 
| Recommended Phase 2 Dose (RP2D) (Dose Escalation Phase) | The RP2D will be determined after reviewing all of the clinically relevant toxicity, efficacy and pharmacokinetic/pharmacodynamic data by the Trial Management Group. | Day 1 to off-study visit (max. 13 months) | 
| Number of Grade 3, 4 and 5 Adverse Events (AEs) Related to TT-702 (Dose Escalation Phase) | Number of Grade 3, 4 and 5 AEs related to TT-702 given as a single agent graded according to National Cancer Institute Common Criteria for Adverse Events (NCI CTCAE) Version 5.0. | Safety data will be collected from the time of informed consent until 21 days after the last dose of TT-702. The average time from consent to the end of follow up will be presented. | 
| Assess Number of Patients with Confirmed Complete Response (CR) and Partial Response (PR) (MSI/MMR and TNBC Arms Expansion Phase) | The number of patients who have a confirmed CR or PR according to Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1. | Radiological assessment within 28 days before starting TT-702; end of every 3 cycles (21-day cycles) up to 6 months then every 4 cycles & treatment discontinuation and/or off-study visit (max. 13 months) | 
| Assess Number of Patients with Confirmed CR and PR (mCRPC Arms Expansion Phase) | The number of patients who have a confirmed CR or PR according to Prostate Cancer Working Group 3 criteria (PCWG3) (encompassing RECIST 1.1 and Prostate Specific Antigen [PSA] level changes) in patients with mCRPC. | Radiological assessment (CT/MRI) within 28 days & bone scan (if required) within 8 weeks before starting TT-702; end of every 3 cycles (21-day cycles) up to 6 months then every 4 cycles & treatment discontinuation and/or off-study visit (max. 13 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of Maximum (or Peak) Plasma Concentration (Cmax) of TT-702 and its Active Product TT-478 as Appropriate (Dose Escalation and Expansion Phase) | Measurement of Cmax of TT-702 and its active product TT-478 as appropriate. | From first dose of TT-702 until discontinuation visit (max. 12 months) | 
| Measurement of Minimal Plasma Concentration (Cmin) of TT-702 and its Active Product TT-478 as Appropriate (Dose Escalation and Expansion Phase) | Measurement of Cmin of TT-702 and its active product TT-478 as appropriate. | From first dose of TT-702 until discontinuation visit (max. 12 months) | 
| Measurement of Time at Cmax (Tmax) of TT-702 and its Active Product TT-478 as Appropriate (Dose Escalation and Expansion Phase) | Measurement of Tmax of TT-702 and its active product TT-478 as appropriate. | From first dose of TT-702 until discontinuation visit (max. 12 months) | 
| Area Under the Curve (AUC) of TT-702 and its Active Product TT-478 as Appropriate (Dose Escalation and Expansion Phase) | AUC of TT-702 and its active product TT-478 as appropriate. | From first dose of TT-702 until discontinuation visit (max. 12 months) | 
| Apparent Clearance of TT-702 and its Active Product TT-478 as Appropriate (Dose Escalation and Expansion Phase) | Apparent clearance of TT-702 and its active product TT-478 as appropriate. | From first dose of TT-702 until discontinuation visit (max. 12 months) | 
| Volume of Distribution of TT-702 and its Active Product TT-478 as Appropriate (Dose Escalation and Expansion Phase) | Volume of Distribution of TT-702 and its active product TT-478 as appropriate. | From first dose of TT-702 until discontinuation visit (max. 12 months) | 
| Terminal Elimination Half-Life (T1/2) of TT-702 and its Active Product TT-478 as Appropriate (Dose Escalation and Expansion Phase) | T1/2 of TT-702 and its active product TT-478 as appropriate. | From first dose of TT-702 until discontinuation visit (max. 12 months) | 
| Duration of Response and of Clinical Benefit Defined as Duration of Confirmed CR, PR or Stable Disease (SD) (Dose Escalation Phase) | The duration of CR, PR or SD according to RECIST Version 1.1 or according to PCWG3 criteria (encompassing RECIST 1.1 and PSA level changes) in patients with mCRPC. | From baseline radiological disease assessment until 21 days after last dose of TT-702 per patient | 
| Number of Patients whose Cancer has not Progressed at Six Months (Dose Escalation and Expansion Phase ) | Number of patients whose cancer has not progressed at six months. | From first dose of TT-702 until six months after first dose of TT-702 | 
| Number of Patients who are still Alive at 12 Months (Dose Escalation and Expansion Phase) | Number of patients who are still alive at 12 months. | From first dose of TT-702 until 12 months after first dose of TT-702 | 
| Number of Grade 3, 4 and 5 AEs related to TT-702 (Dose Expansion Phase) | Number of Grade 3, 4 and 5 AEs related to TT-702 given as a single agent graded according to NCI CTCAE Version 5.0. | Safety data will be collected from the time of informed consent until 21 days after the last dose of TT-702. The average time from consent to the end of follow up will be presented | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adenosine receptors, MSI Deficient Cancers, MMR Deficient Cancer, Castrate resistant Prostate Cancer, Triple Negative Breast Cancer