Trial Title:
HTL0039732 in Participants With Advanced Solid Tumours
NCT ID:
NCT05944237
Condition:
Neoplasms
Prostatic Neoplasms, Castration-Resistant
Stomach Neoplasms
Esophageal Neoplasms
Head and Neck Neoplasms
Colorectal Neoplasms
Pancreatic Neoplasms
Lung Neoplasms
Urinary Bladder Neoplasms
Mesothelioma, Malignant
Uterine Cervical Neoplasms
Kidney Neoplasms
Sarcoma
Pheochromocytomas
Conditions: Official terms:
Neoplasms
Mesothelioma
Mesothelioma, Malignant
Colorectal Neoplasms
Prostatic Neoplasms
Lung Neoplasms
Pancreatic Neoplasms
Head and Neck Neoplasms
Pheochromocytoma
Stomach Neoplasms
Esophageal Neoplasms
Uterine Cervical Neoplasms
Urinary Bladder Neoplasms
Kidney Neoplasms
Prostatic Neoplasms, Castration-Resistant
Atezolizumab
Conditions: Keywords:
EP4 antagonist
Anti-PD-1/PD-L1 agents
PGE2
EP4
COX inhibitor
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
HTL0039732 Capsules
Description:
HTL0039732 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.
Arm group label:
Phase 1 Part A HTL0039732 (Dose Escalation Monotherapy)
Intervention type:
Drug
Intervention name:
HTL0039732 Capsules and atezolizumab infusion
Description:
HTL0039732 Capsules will be administered orally on a QD schedule to fasted participants
starting on Cycle 1 Day 1. Each administration cycle will consist of 21 days with no
break between cycles. Cycle 1 will consist of HTL0039732 monotherapy. From Cycle 2
onwards, participants will also receive 1200 mg atezolizumab as an IV infusion on Day1 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.
Arm group label:
Phase 1 Part B HTL0039732 and Atezolizumab (Dose Escalation Combination)
Arm group label:
Phase 2a HTL0039732 and Atezolizumab (Dose Expansion Combination)
Summary:
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.
Detailed description:
The trial will investigate HTL0039732, a novel specific E-type prostanoid receptor 4
(EP4) antagonist, as a monotherapy and in combination with atezolizumab, a monoclonal
antibody that binds to the programmed death ligand 1 (PD-L1). The trial may be expanded
in future to also evaluate HTL0039732 in combination with other approved anti-cancer
therapies. HTL0039732 is a small molecule drug that blocks activation of EP4 receptors by
prostaglandin E2, a naturally occurring substance in the body.
Prostaglandin E2 may be elevated in cancer and signalling via the EP4 receptor can lead
to suppression of immune activity, allowing the cancer to escape from the immune system.
Blocking the EP4 receptor may relieve that immunosuppression, allowing the immune system
to be active against the cancer again.
Atezolizumab is an established immune checkpoint inhibitor that overcomes a key
immunosuppressive signal and improves the magnitude and quality of tumour-specific T-cell
responses, resulting in improved anti-cancer activity. It, and other similar agents, are
approved for the treatment of several different types of cancer. As a common mechanism of
immune suppression, immune checkpoint inhibitors also have a role in combination
immunotherapies and combining EP4 inhibition by HTL0039732 with PD-L1 blockade by
atezolizumab, is expected to have increased activity.
The trial will investigate HTL0039732 as a monotherapy and in combination with
atezolizumab, and potentially with other approved anti-cancer therapies, in participants
with advanced solid tumours (Phase 1 Part A) and in participants with advanced solid
tumours where PGE2/EP4 signalling is believed to be more prevalent or significant (Phase
1 Part B and Phase 2a).
This is a first-in-human clinical trial and is split as follows:
- Phase 1 is the 'dose escalation' phase, where two groups (known as Part A and Part
B) of participants with solid tumours will receive increasing doses of HTL0039732 to
find the safest dose.
- Part A participants will receive HTL0039732 as a single agent.
- Part B participants will receive HTL0039732 in combination with atezolizumab.
- More Parts may be added in future for participants to receive HTL0039732 in
combination with other approved anti-cancer therapies.
- Phase 2a is the 'dose expansion' phase, where participants grouped according to the
type of cancer they have will receive the recommended Phase 2 dose of HTL0039732 in
combination with atezolizumab, and potentially in combination with other approved
anti-cancer therapies. Phase 2a will follow a response enrichment approach; activity
of the investigational medicinal products will be assessed in each group and ongoing
recruitment will focus on tumour types with promising signals.
The main aims of the clinical trial are to find out:
- The most appropriate dose of HTL0039732 administered on its own, and the most
appropriate dose/s of HTL0039732 to take forward for further investigation in
combination with atezolizumab and with other approved anti-cancer therapies.
- More about any potential side effects of HTL0039732 when given alone and in
combination with atezolizumab and other approved anti-cancer therapies.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Written (signed and dated) informed consent and capable of co-operating with
investigational medicinal product administration and follow-up.
2. Phase 1, dose escalation phase
Part A (HTL00397932 monotherapy):
- 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.
i. Previously irradiated lesions cannot be counted as target lesions unless
clearly progressed after radiotherapy.
- Consent to access and analysis of any available archival tissue or a fresh
tumour sample at baseline, if archival tissue is unavailable.
- Consent for fresh tumour biopsy sample(s) at time of PD, if the participant has
accessible disease and is eligible to receive atezolizumab.
Phase 1 Part B:
- Histologically proven advanced solid tumour where PGE2/EP4 signalling is
believed to be more prevalent or significant (such as microsatellite stable
colorectal cancer (MSS CRC), gastro-esophageal cancer, head and neck squamous
cell carcinoma (HNSCC), mCRPC, pancreatic cancer, lung cancer, bladder cancer,
mesothelioma, cervical cancer, renal cancer, sarcoma, pheochromocytoma and
cancers with PI3K/AKT/mTOR pathway activating mutations using a
clinically-validated assay).
Phase 2a:
- Histologically proven advanced solid tumour, with the exact indications to be
confirmed based on results observed in Phase I Part B, refractory to
conventional treatment, or for which no conventional therapy is considered
appropriate by the Investigator or is declined by the potential participant.
Phase 1 Part B and Phase 2a:
- Consent to access and analysis of any available archival tissue.
- Consent for fresh tumour biopsy samples at baseline and on trial.
- Disease refractory to conventional treatment, or for which no further
conventional therapy is considered appropriate by the Investigator or is
declined by the participant.
- Except for mCRPC, 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. Potential participants with mCRPC must have PD
according to PCWG3 criteria.
- i. Previously irradiated lesions cannot be counted as target lesions
unless clearly progressed after the radiotherapy.
- ii. Lesions that are intended to be biopsied should not be counted as
target lesions (those undergoing biopsy must have at least one target
lesion that is not intended to be biopsied).
3. Life expectancy of at least 12 weeks.
4. Eastern Cooperative Oncology Group performance status of 0 or 1.
5. Haematological and biochemical indices within the protocol specified ranges.
6. Stable thyroid function tests. Stable doses of thyroxine replacement are permitted.
7. Aged 18 years or over at the time consent is given.
Exclusion Criteria:
1. 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.
2. Ongoing toxic manifestations of previous treatments that are Grade ≥1 per CTCAE
v5.0.
3. 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).
4. Women of child-bearing potential (or who are already pregnant or lactating).
Exceptions apply.
5. Men with partners of childbearing potential. Exceptions apply.
6. Major thoracic or abdominal surgery from which the potential participant has not yet
recovered.
7. At high medical risk because of non-malignant systemic disease, including active
uncontrolled infection.
8. Known history of current or latent tuberculosis, HIV or Hepatitis B or C infection.
9. Prior treatment with EP4 inhibitor.
10. Treatment with selective cyclooxygenase-2 inhibitor in the 8 weeks prior to
enrolment.
11. Known hypersensitivity or intolerance to hydroxypropyl methylcellulose.
12. Use of systemic immunosuppressive agent in the 2 weeks prior to enrolment.
Exceptions apply.
13. Significant cardiovascular disease.
14. Known active peptic ulcer disease, or symptoms of gastritis, dyspepsia or
gastro-esophageal reflux disease (one or more episodes per week).
15. Current or planned participation in another interventional clinical trial, whilst
taking part in this trial of HTL0039732.
16. Limited ability to swallow or absorb oral medications.
17. Any other condition that, in the Investigator's opinion, would mean that the trial
is not in the best interests of the potential participant.
Phase 1 Part B and Phase 2a:
18. Any live vaccines in the 4 weeks prior to enrolment.
19. Diagnosis of immunodeficiency.
20. Active autoimmune disease requiring systemic treatment in the 2 years prior to
enrolment.
21. History or clinical suspicion of interstitial lung disease, history of
(non-infectious) pneumonitis that required steroids, or current pneumonitis.
22. Hypersensitivity to atezolizumab or any of its excipients.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Addenbrooke's Hospital
Address:
City:
Cambridge
Zip:
CB2 0QQ
Country:
United Kingdom
Status:
Recruiting
Contact:
Last name:
Bristi Basu, Dr
Phone:
01223 596105
Email:
Bristi.Basu@nhs.net
Facility:
Name:
Velindre Cancer Centre
Address:
City:
Cardiff
Zip:
CF14 2TL
Country:
United Kingdom
Status:
Not yet recruiting
Contact:
Last name:
Robert Jones, Dr
Phone:
02920 615888 Ext 6327
Email:
Robert.Hugh.Jones@wales.nhs.uk
Facility:
Name:
Clatterbridge Cancer Centre
Address:
City:
Liverpool
Zip:
CH63 4JY
Country:
United Kingdom
Status:
Not yet recruiting
Contact:
Last name:
Daniel Palmer, Prof
Phone:
0151 706 4172 / 0151 706 4177
Email:
palmerd@liverpool.ac.uk
Facility:
Name:
Guy's Hospital
Address:
City:
London
Zip:
SE1 9RT
Country:
United Kingdom
Status:
Recruiting
Contact:
Last name:
Debashis Sarker, Dr
Phone:
020 7188 4249
Email:
Debashis.Sarker@kcl.ac.uk
Facility:
Name:
The Christie Hospital
Address:
City:
Manchester
Zip:
M20 4BX
Country:
United Kingdom
Status:
Recruiting
Contact:
Last name:
Natalie Cook, Dr
Phone:
0161 918 7672
Email:
Natalie.Cook17@nhs.net
Start date:
July 13, 2023
Completion date:
September 2026
Lead sponsor:
Agency:
Cancer Research UK
Agency class:
Other
Collaborator:
Agency:
Nxera Pharma UK Limited
Agency class:
Industry
Source:
Cancer Research UK
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05944237
