The purpose of this trial is to evaluate a new drug, HTL0039732, that will be administered on its own (as a monotherapy) and in combination with atezolizumab or with other approved anti-cancer therapies, in participants with advanced solid tumours.
Written (signed and dated) informed consent and capable of co-operating with investigational medicinal product administration and follow-up.
Phase 1, dose escalation phase
Histologically or cytologically proven advanced solid tumour, refractory to conventional treatment, or for which no further conventional therapy is considered appropriate by the Investigator or is declined by the potential participant.
At least 1 measurable lesion according to RECIST v1.1, which (in the Investigator's opinion) has had objective radiological progression on or after the last therapy, or at least one assessable lesion e.g. pleural or peritoneal thickening that does not fulfil RECIST v1.1 criteria for measurable disease.
Radiotherapy (except for palliative reasons), chemotherapy, non chemotherapy systemic anti-cancer therapy (apart from life-long hormone suppression such as luteinising hormone-releasing agents in participants with mCRPC) or investigational medicinal products during the 4 weeks prior to enrolment; or first dose of an immunotherapy during the previous 12 weeks before first dose of HTL0039732.
Ongoing toxic manifestations of previous treatments that are Grade >1 per CTCAE v5.0.
Any central nervous system metastases (unless potential participants have had local therapy and are asymptomatic, radiologically stable and have been off steroids for ≥4 weeks prior to enrolment).
Women of child-bearing potential (or who are already pregnant or lactating). Exceptions apply.
Parallel
HTL0039732 Capsules
DrugHTL0039732 Capsules will be administered orally to fasted participants, although an exploration of food effects may be performed as a single dose at Cycle 0. A single dose will be administered between 3 and 9 days prior to commencement of Cycle 1. From Cycle 1 Day 1, HTL0039732 will be administered on a once daily (QD) schedule. Each administration cycle will consist of 21 days with no break between cycles. Participants may initially receive up to 18 cycles but may continue for a further 18 cycles if they are deemed to be benefitting.
HTL0039732 Capsules or HTL0039732 tablets and atezolizumab infusion
DrugHTL0039732 Capsules or HTL0039732 tablets will be administered orally on a QD schedule to participants starting on Cycle 1 Day 1. Each administration cycle will consist of 21 days with no break between cycles. Participants will also receive 1200 mg atezolizumab as an IV infusion on Day 1 of each cycle (i.e. every 3 weeks). Participants may initially receive up to 18 cycles of HTL0039732 but may continue for a further 18 cycles if they are deemed to be benefitting, and they may receive up to 36 cycles of atezolizumab.
Maximum tolerated dose (MTD; Dose Escalation Phase)
The MTD is the highest dose of HTL0039732 in the safe dose range, i.e. where there is a \<25% probability of toxicity being above 30%.
RP2D (Dose Escalation Phase)
The RP2D for HTL0039732 will be determined after reviewing all of the clinically relevant toxicity, efficacy and pharmacokinetic (PK)/pharmacodynamic data by the Trial Management Group.
Number of Adverse Events (AEs) Related to HTL0039732 (Dose Escalation and Expansion Phase)
Number of all grade AEs, and number of Grade 3, 4 and 5 AEs, considered at least possibly related to HTL0039732, graded according to National Cancer Institute Common Criteria for Adverse Events (NCI CTCAE) Version 5.0. Count of AEs by arm.
Number of AEs Related to Atezolizumab (Dose Escalation and Expansion Phase)
Number of all grade AEs, and number of Grade 3, 4 and 5 AEs, considered at least possibly related to atezolizumab, graded according to NCI CTCAE Version 5.0. Count of AEs by arm.
Measurement of the PK Parameter Maximum (or Peak) Plasma Concentration (Cmax) of HTL0039732 (Dose Escalation and Expansion Phase)
Plasma samples will be analysed by liquid chromatography with tandem mass spectrometry (LC-MS/MS) to determine the Cmax of HTL0039732 after oral administration of HTL0039732 as monotherapy and in combination with atezolizumab, according to agreed standard operating procedures (SOPs) and validated methods. Not all participants may be analysed at all time points.
Measurement of the PK Parameter Time to Reach Maximum (or Peak) Plasma Concentration (Tmax) of HTL0039732 (Dose Escalation and Expansion Phase)
Plasma samples will be analysed by LC-MS/MS to determine the Tmax of HTL0039732 after oral administration of HTL0039732 as monotherapy and in combination with atezolizumab, according to agreed SOPs and validated methods. Not all participants may be analysed at all time points.
Measurement of the PK Parameter Minimum Plasma Concentration (Cmin) of HTL0039732 (Dose Escalation and Expansion Phase)
Plasma samples will be analysed by LC-MS/MS to determine the Cmin of HTL0039732 after oral administration of HTL0039732 as monotherapy and in combination with atezolizumab, according to agreed SOPs and validated methods. Not all participants may be analysed at all time points.
Measurement of the PK Parameter Area under the Plasma Concentration-Time Curve (AUC) (Dose Escalation and Expansion Phase)
Plasma samples will be analysed by LC-MS/MS to determine the AUC of HTL0039732 after oral administration of HTL0039732 as monotherapy and in combination with atezolizumab, according to agreed SOPs and validated methods. Not all participants may be analysed at all time points.
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Cancer Research UK
Lead sponsor
Nxera Pharma UK Limited
Collaborator
