A Phase 1/2 interventional study of TT-702 and Anti-PD-1 and PD-L1 agent in Advanced Solid Tumors, sponsored by Cancer Research UK. Recruiting at 3 sites in United Kingdom. Open to participants aged 16 Years and older. Per ClinicalTrials.gov, last updated 2026-08-12.
Sponsored by Cancer Research UK · Phase 1/2, Interventional, and Treatment
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.
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:
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:
MMRd tumour, confirmed by either:
i. Loss of MSH2, MSH6, MLH1, PMS2 by ICH (total or near total) OR ii. Loss of function mutation f MMR gene(s) AND iii. High tumour mutation burden (depends on assay but typically >15 mutations/MB sequenced).
Non-MMRd tumours:
mCRPC: - Prior treatment with a next generation hormonal agent. - Adenocarcinoma without neuroendocrine or small cell features.
TNBC:
- Human epidermal growth factor receptor 2 negativity (negative immunohistochemistry [IHC] staining [score 0 or 1] or negative fluorescence in situ hybridisation 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/ISO 15198 scope of accreditation.
CRC, NSCLC and PDAC:
- Histologically or cytologically proven diagnosis of CRC, NSCLC or PDAC
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 cohort) and Cohort 2P (TT-702 \& anti-PD-1/PD-L1 combination cohort):
MMRd tumour, confirmed by either:
i. Loss of MSH2, MSH6, MLH1, PMS2 by IHC (total or near total) OR ii. Loss of function mutation of MMR gene(s) AND iii. High tumour mutation burden (depends on assay but typically >15 mutations/MB sequenced).
Exclusion criteria:
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Women of childbearing potential (or are already pregnant or lactating). However, those patients who meet the following points are considered eligible:
Male patients with partners of childbearing potential. However, those patients who meet the following points are considered eligible:
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:
a. History of congestive heart failure requiring therapy (NYHA III or IV); b. History of unstable angina pectoris or myocardial infarction up to six months prior to trial entry (patients with previous cardiac or thrombotic events who are now stable and or recovered are eligible); c. Presence of severe valvular heart disease; d. Presence of a ventricular arrhythmia requiring treatment; e. Left ventricular ejection fraction \< 50%; f. Has a QTcF prolongation to >470 milliseconds (ms) based on a 12-lead ECG in triplicate; g. Previous stroke or transient ischaemic attack within 6 months of trial entry; h. History of clinically significant peripheral vascular disease/vasculitis/vasculopathy.
Patients with a known or suspected history of hypersensitivity or allergy to TT-702, or any of its excipients (for any strength) are excluded:
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.
This cohort will recruit patients with MMRd tumours or non-MMRd CRC, mCRPC, NSCLC, PDAC, TNBC.
Drug: TT-702
This cohort will recruit patients with MMR defective tumours who have had prior treatment with an immune checkpoint inhibitor (ICI).
Drug: TT-702
This cohort will recruit patients who have had prior treatment with an ICI.
Drug: Anti-PD-1 and PD-L1 agent
This cohort will recruit patients with MMRd tumours who have had prior treatment with an ICI.
Drug: Anti-PD-1 and PD-L1 agent
TT-702 will be administered orally, once daily, for up to 12 months.
An appropriate anti-PD-1/PD-L1 combination agent will be selected and implemented following a substantial amendment.
Number of Dose Limiting Toxicities (DLTs) (Dose Escalation Phase)
Dose Limiting Toxicities to TT-702 are determined by testing increasing doses of TT-702 administered once daily in continuous 21-day cycles in escalation cohorts. Dose limiting toxicities are defined per protocol as a highly probably or probably TT-702-related adverse events (AEs) of neutropenia, thrombocytopenia, non-haematological toxicities, photosensitivity, death or other drug-related toxicity causing TT-702 interruption, occurring during Cycle 0 or Cycle 1 administration.
Time frame: From the first dose in Cycle 0, until completion of Cycle 1 (3 weeks [+ 3-9 days to account for initial pharmacokinetic (PK) profiling period following the Cycle 0 dose]).
Number of Treatment-Emergent AEs (TEAEs), Related TEAEs and Grade 3, 4 or 5 TEAEs (Dose Escalation Phase)
Number of TEAEs, TEAEs related to TT-702 and Grade 3, 4 or 5 TEAEs in the dose escalation phase. AEs are categorised according to Medical Dictionary for Regulatory Activities (MedDRA) and graded for severity according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) versions applicable at time of reporting. AEs are assessed by the reporting study doctors for a causal relationship to TT-702. Related are those AEs with a causality of possible, probable or highly probable. All AEs are collected until the off-study visit, approximately 21 (±7) days after the final dose of TT-702 and TT-702-related AEs present at the off-study visit are to be followed up monthly until resolution, return to baseline, stabilisation or initiation of another anti-cancer treatment.
Time frame: From the time of first dose until the end of the safety follow-up period for TT-702.
Objective Response Rate (ORR)
ORR is defined as the proportion of participants with a confirmed Complete Response (CR) or Partial Response (PR) at 6 months (Expansion Phase) and is used to assess antitumour activity according to PCWG3 or RECIST v1.1 criteria. Responses must be confirmed by repeat assessment ≥4 weeks after initial response criteria are met.
Time frame: From the first dose and until the final radiological disease assessment at the off-study visit.
Number and Percentage of Participants that Achieved Clinical Benefit Assessed by PCWG3 and RECIST v1.1 (Expansion Phase)
Antitumour activity measured according to PCWG3 and RECIST version 1.1. Complete Response or PR/remission is confirmed by repeat measurements ≥4 weeks after response criteria are met; participants with SD are to meet criteria at least once ≥6 weeks after first dose of TT-702. Clinical Benefit Rate is defined as the proportion of participants with absence of disease progression (i.e. confirmed CR, PR or SD) for at least 24 weeks from the start of trial treatment.
Time frame: From the first dose and until the final radiological disease assessment at the off-study visit.
Measurement of Maximum (or Peak) Plasma Concentration (Cmax) of TT-702 and its Active Product, TT-478, as Appropriate (Dose Escalation and Expansion Phase)
Pharmacokinetic parameters are derived from analysing the concentration of TT-702 and its active metabolite, TT-478, in plasma via Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS).
Time frame: From the first dose of TT-702 until the 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)
Pharmacokinetic parameters are derived from analysing the concentration of TT-702 and its active metabolite, TT-478, in plasma via LC-MS/MS.
Time frame: From the first dose of TT-702 until the 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)
Pharmacokinetic parameters are derived from analysing the concentration of TT-702 and its active metabolite, TT-478, in plasma via LC-MS/MS.
Time frame: From the first dose of TT-702 until the 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)
Pharmacokinetic parameters are derived from analysing the concentration of TT-702 and its active metabolite, TT-478, in plasma via LC-MS/MS.
Time frame: From the first dose of TT-702 until the discontinuation visit (max 12 months).
Apparent Clearance of TT-702 and its Active Product, TT-478, as Appropriate (Dose Escalation and Expansion Phase)
Pharmacokinetic parameters are derived from analysing the concentration of TT-702 and its active metabolite, TT-478, in plasma via LC-MS/MS.
Time frame: From the first dose of TT-702 until the discontinuation visit (max 12 months).
Volume of Distribution of TT-702 and its Active Product, TT-478, as Appropriate (Dose Escalation and Expansion Phase)
Pharmacokinetic parameters are derived from analysing the concentration of TT-702 and its active metabolite, TT-478, in plasma via LC-MS/MS.
Time frame: From the first dose of TT-702 until the 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)
Pharmacokinetic parameters are derived from analysing the concentration of TT-702 and its active metabolite, TT-478, in plasma via LC-MS/MS.
Time frame: From the first dose of TT-702 until the discontinuation visit (max 12 months).
Objective Response Rate Defined as the Proportion of Participants with Confirmed CR or PR According to PCWG3 or RECIST v1.1 at 6 Months (Dose Escalation Phase)
Antitumour activity via ORR measured according to PCWG3 (cRPC) and RECIST v1.1 (solid tumours). Complete Response or PR/remission is to be confirmed by repeat measurements ≥4 weeks after response criteria are met.
Time frame: From the first dose until the final radiological assessment at the off-study visit.
Number and Percentage of Participants that Achieved Clinical Benefit Assessed by PCWG3 or RECIST v1.1 (Dose Escalation Phase)
Antitumour activity measured according to PCWG3 (cRPC) and RECIST version 1.1 (solid tumours). Complete response or PR/remission is confirmed by repeat measurements ≥4 weeks after response criteria are met; participants with SD are to meet criteria at least once ≥6 weeks after first dose of TT-702. Clinical benefit rate is defined as the proportion of participants with absence of disease progression (i.e. confirmed CR, PR or SD) for at least 24 weeks from the start of trial treatment.
Time frame: From the first dose and until the final radiological disease assessment at the off-study visit.
Objective Response Rate Defined as the Proportion of Participants with Confirmed CR or PR According to PCWG3 or RECIST v1.1 at Cycles 3, 6, 9, 12 (Dose Escalation and Expansion Phase)
Antitumour activity measured according to PCWG3 (cRPC) and RECIST version 1.1 (solid tumours). Complete response or PR/remission is confirmed by repeat measurements ≥4 weeks after response criteria are met.
Time frame: From the first dose and until the final radiological disease assessment at the off-study visit.
Objective Response Rate Defined as the Proportion of Participants with Confirmed CR or PR According to PCWG3 or RECIST v1.1 at Any Timepoint (Dose Escalation and Expansion Phase)
Antitumour activity measured according to PCWG3 (cRPC) and RECIST version 1.1 (solid tumours). Complete response or PR/remission is confirmed by repeat measurements ≥4 weeks after response criteria are met.
Time frame: From the first dose and until the final radiological disease assessment at the off-study visit.
Median Duration of Response and 90% Confidence Interval for Participants that Achieved a Confirmed Response (Dose Escalation and Expansion Phase)
Antitumour activity measured according to PCWG3 (cRPC) and RECIST version 1.1 (solid tumours). Complete response or PR/remission is confirmed by repeat measurements ≥4 weeks after response criteria are met. Duration of response is defined as the time from the first observation of CR or PR to PD or death from any cause in participants with confirmed CR or PR.
Time frame: From the first dose and until the final radiological disease assessment at the off-study visit.
Median Duration of Clinical Benefit and 90% Confidence Interval for Participants that Achieved Clinical Benefit (Dose Escalation and Expansion Phase)
Antitumour activity measured according to PCWG3 (cRPC) and RECIST version 1.1 (solid tumours). Complete response or PR/remission is confirmed by repeat measurements ≥4 weeks after response criteria are met; participants with SD are to meet criteria at least once ≥6 weeks after first dose of TT-702. Duration of clinical benefit is defined as duration from date of first administration of TT-702 to PD or death from any cause in participants with confirmed CR, PR or SD for at least 24 weeks from date of administration of the first dose of TT-702.
Time frame: From the first dose and until the final radiological disease assessment at the off-study visit.
Number and Percentage of Participants who Remained Progression Free at 6 Months with 90% Confidence Intervals (Dose Escalation and Expansion Phase)
Antitumour activity measured according to PCWG3 (cRPC) and RECIST version 1.1 (solid tumours). Complete or partial response/remission is confirmed by repeat measurements ≥4 weeks after response criteria are met; participants with SD met criteria at least once ≥6 weeks after first dose of TT-702.
Time frame: From the first dose and until confirmation of progression, at the 6-month timepoint.
Number and Percentage of Participants who are Alive at 12 Months with Associated 90% Confidence Intervals (Dose Escalation and Expansion Phase)
Overall survival of participants at the 12 month post-first dose timepoint.
Time frame: From the first dose and until confirmation of alive or deceased from any cause, at the 12-month timepoint.
Number of TEAEs, related TEAEs, and Grade 3, 4 or 4 TEAEs (Dose Expansion Phase)
Number of TEAEs, TEAEs related to TT-702 and Grade 3, 4 or 5 TEAEs in the dose expansion phase. Adverse events are categorised according to MedDRA and graded for severity according to NCI CTCAE versions applicable at time of reporting. Adverse events are assessed by the reporting study doctors for a causal relationship to TT-702. Related are those AEs with a causality of possible, probable or highly probable. All AEs are collected until the off-study visit, approximately 21 (±7) days after the final dose of TT-702 and TT-702-related AEs present at the off-study visit are to be followed up monthly until resolution, return to baseline, stabilisation or initiation of another anti-cancer treatment.
Time frame: From the time of first dose until the end of the safety follow-up period for TT-702.
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