A Modular, Multi-part, Multi-arm, Open-label, Phase I/II Study to Evaluate the Safety and Tolerability of GRWD5769 Alone and in Combination with Anticancer Treatments in Patients with Solid Malignancies

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Grey Wolf Therapeutics Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

5 Oct 2023 → ongoing

Decision date (initial)

2025-01-29

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Grey Wolf Therapeutics Limited

External identifiers

EU CT number

2023-504845-30-00

ISRCTN

ISRCTN45104480

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Pharmacogenomic, Dose response, Safety, Pharmacodynamic, Pharmacokinetic, Efficacy

Module 1: To determine the safety and tolerability of GRWD5769 monotherapy in participants with advanced malignancies.
Module 2 Part A - C: To determine the safety and tolerability of GRWD5769 when administered in combination with cemiplimab (Libtayo®) 350 mg.
Module 2 Part D: To compare the efficacy of 3 doses of GRWD5769 randomised 1:1:1.

Secondary objectives 9

1. Module 1: To determine the MTD (if any) and/or RP2D of GRWD5769 monotherapy.
2. Module 2 Part A - C: To determine the MTD (if any) and/or RP2D of GRWD5769 when administered in combination with cemiplimab 350 mg.
3. Module 1: To characterise the plasma PK of GRWD5769 monotherapy, following single and multiple dose administration.
4. Module 2: To evaluate plasma accumulation of GRWD5769 when administered in combination with cemiplimab 350 mg.
5. Module 1: To assess the preliminary efficacy of GRWD5769 when administered as a monotherapy.
6. Module 2: To assess the preliminary efficacy of GRWD5769 when administered in combination with cemiplimab 350 mg.
7. Module 1: To identify the MBAD of GRWD5769 when administered as a monotherapy.
8. Module 2: To identify the MBAD of GRWD5769 when administered in combination with cemiplimab 350 mg.
9. Module 2 Part D: To determine the safety and tolerability of GRWD5769 when administered in combination with cemiplimab (Libtayo®) 350 mg.

Conditions and MedDRA coding

Solid malignancies

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 29

1. All Modules: Must have given written informed consent before any study-related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects.
2. Cervical Cancer (Cohort 1 of Module 2 Part C): Participants may enrol in the study immediately following progression on the first line CPI or may have received 1 further line of systemic cancer therapy after progression on CPI.
3. Hepatocellular Carcinoma (Cohort 2 of Module 2 Part C): Participant has Child-Pugh score class A liver function
4. Module 1 (Parts A, B and C) and Module 2 (Parts A and B): Participant has cytologically or histologically confirmed locally advanced or metastatic solid malignancy for which no further standard of care (SoC) therapy is available (or no SoC therapy exists), or who have been offered and declined SoC therapy, or are intolerant of SoC therapy.
5. Moderate to High TMB (Cohort 3 of Module 2 Part C): Participants with cytologically or histologically confirmed advanced, recurrent or metastatic disease, which is not amenable to curative therapy, in up to 5 types of solid tumour with moderate to high median TMB (NSCLC, urothelial, SCCHN, gastric/gastro-oesophageal adenocarcinoma, oesophageal SCC). • Note - gastric/gastro-oesophageal adenocarcinoma and oesophageal SCC indications will not open in France. Participants should have received ≥ 3 months first line anti-PD-(L)1 therapy fulfilling one of the qualifying criteria below and have completed at least a 10-week period without progression per Investigator assessment o Anti-PD-(L)1 therapy initiated without chemotherapy, either as monotherapy or in combination with other immunotherapy e.g. anti-CTLA-4 o Following completion of chemotherapy (e.g. platinum-based chemotherapy) ± anti PD-(L)1 therapy § for NSCLC continuation of pemetrexed treatment following completion of chemotherapy is permitted o Anti-PD-(L)1 therapy in combination with an ADC e.g. enfortumab vedotin (EV) § If the ADC is discontinued, participants remaining on anti-PD-(L)1 therapy for ≥3 months total duration are still eligible
6. Hepatocellular Carcinoma (Cohort 2 of Module 2 Part C): Participants may enrol in the study immediately following progression on the first line CPI or may have received 1 further line of systemic cancer therapy after progression on CPI.
7. Module 1 (Parts A, B and C) and Module 2 (Parts A and B): Participant has measurable disease per RECIST 1.1/iRECIST.
8. Module 1 (Part B) and Module 2 (Part B): Participant has at least one tumour lesion amenable to serial biopsies and is willing to provide consent for biopsies and has measurable disease per RECIST 1.1/iRECIST, excluding the lesion(s) identified for biopsy.
9. Cervical Cancer (Cohort 1 of Module 2 Part C): Participants with histologically confirmed persistent, recurrent or metastatic cervical cancer (SCC, adenocarcinoma, and adenosquamous carcinoma) who are not amenable to curative therapy.
10. Cervical Cancer (Cohort 1 of Module 2 Part C): Participants should have received ≥ 3 months first line anti-PD(L)-1 therapy fulfilling one of the qualifying criteria below and completed at least a 10-week period without progression per investigator assessment:o Anti-PD-(L)1 therapy initiated without chemotherapy, either as monotherapy or in combination with other immunotherapy e.g. anti-CTLA-4 o Following completion of chemotherapy (e.g. platinum-based chemotherapy) ± anti PD-(L)1 therapy § Continuation or initiation of bevacizumab treatment following completion of chemotherapy is permitted o Anti-PD-(L)1 therapy in combination with an Antibody Drug Conjugate (ADC) e.g. enfortumab vedotin (EV) § If the ADC is discontinued, participants remaining on anti-PD-(L)1 therapy for ≥3 months total duration are still eligible
11. All Modules: Willing to permit access to stored historical tumour tissue and prior tumour radiological assessments and tumour biomarker data (if available).
12. Moderate to High TMB (Cohort 3 of Module 2 Part C): Participants may enrol in the study immediately following progression on the first line CPI or may have received 1 further line of systemic cancer therapy after progression on CPI. Specific requirements in France • Urothelial cancer - participants may only enrol after first line CPI if they are not eligible to be treated in second line with platinum-based chemotherapy, erdafitinib or EV monotherapy or if eligible, that the treatment is unavailable in the local healthcare system. • For NSCLC, participants may only enrol after first line CPI if they are not eligible to receive second line platinum-based chemotherapy.
13. All Modules: Male or female, ≥ 18 years of age.
14. All Modules: An ECOG performance status of 0 or 1, as determined on the day of first dose administration of IMP (prior to dose administration), or r (for Module 2 Part D) as determined prior to randomisation.
15. Hepatocellular Carcinoma (Cohort 2 of Module 2 Part C): Participants should have received ≥ 3 months first line anti-PD(L)-1 containing therapy and this should have included at least a 10-week period without progression per Investigator assessment.
16. All Modules: Able to take oral medications and be willing to record daily adherence to the study drug.
17. All Modules: Female participants must be of non-childbearing potential i.e., surgically sterilised (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before the screening visit) or post-menopausal (where post-menopausal is defined as no menses for 12 months without an alternative medical cause and if post menopausal within the 6 months prior to the screening visit a follicle stimulating hormone (FSH) level consistent with post-menopausal status, per local laboratory guidelines), or, if of childbearing potential: a. Must have a negative serum pregnancy test at the screening visit and a negative urine pregnancy test within 24 hours prior to the start of study drug or (for Module 2 Part D) prior to randomisation b. Must agree not to attempt to become pregnant c. Must not donate ova from signing consent until at least: i. 33 days (30 days + minimum of 5 x half-lives of GRWD5769) after the last dose of study drug (Module 1) ii. 6 months after the last dose of cemiplimab (Module 2 or Module 1 Part A crossover) d. If not exclusively in a same sex relationship, must agree to use adequate contraception (which is defined as use of a condom by the male partner combined with use of a highly effective method of contraception [Section 23.1]) from signing the consent form until at least 6 months after the last does if study drug (Module 1 and Module 2) and 6 months after the last dose of cemiplimab (Module 2 or Module 1 Part A crossover)
18. All Modules: Male participants must: a. Agree not to donate sperm from the time of signing consent until at least 93 days (90 days + minimum of 5 x half-lives of GRWD5769) after the last dose of study drug; b. If engaging in sexual intercourse with a female partner who could become pregnant, must agree to use a condom plus a highly effective method of contraception (Section 23.1) from the time of signing consent until at least 93 days after the last dose of study drug; c. If engaging in sexual intercourse with a female partner who is not of childbearing potential or a same sex partner, must agree to use a condom from the time of signing consent until at least 93 days after the last dose of study drug.
19. All Modules: Estimated life expectancy of at least 3 months, in the opinion of the PI.
20. All Modules: Willing and able to comply with all scheduled visits, treatment plans, laboratory tests, and other study procedures.
21. Hepatocellular Carcinoma (Cohort 2 of Module 2 Part C): Participants with histologically confirmed hepatocellular carcinoma who are not amenable to curative therapy and ineligible for loco-regional therapy.
22. Cervical Cancer (Cohort 1 of Module 2 Part C): Participant has measurable disease per RECIST 1.1/iRECIST.
23. Hepatocellular Carcinoma (Cohort 2 of Module 2 Part C): Participant has measurable disease per RECIST 1.1/iRECIST.
24. Moderate to High TMB (Cohort 3 of Module 2 Part C): Participant has measurable disease per RECIST 1.1/iRECIST.
25. Module 2 Part D (pMMR/MSS-CRC): Participants with histologically confirmed unresectable pMMR/MSS-CRC, without current or prior liver metastases o pMMR/MSS status to be determined by standard local testing method
26. Module 2 Part D (pMMR/MSS-CRC): Patients with purely peritoneal disease are excluded (see exclusion criteria in Section 9.3 of the Protocol)
27. Module 2 Part D (pMMR/MSS-CRC): Participants should have received at least one line of therapy in the advanced/metastatic setting and should been exposed to fluoropyrimidine, oxaliplatin and irinotecan containing chemotherapy as well as antiangiogenics, anti-EGFR and tumour mutation directed therapies according to local standard practice, unless ineligible or intolerant to the treatment o Participants may not have received more than 2 lines of cytotoxic chemotherapy
28. Module 2 Part D (pMMR/MSS-CRC): Participants may not have had prior CPI / immunotherapy (see exclusion criteria, section 9.3 of the Protocol)
29. Module 2 Part D (pMMR/MSS-CRC): Participant has measurable disease per RECIST 1.1/iRECIST.

Exclusion criteria 34

1. All Modules: Prior therapy with an ERAP1 inhibitor, within any timeframe prior to the first dose of IMP, or (for Module 2 Part D) prior to randomisation.
2. All Modules: Liver function deteriorating in a manner that would likely make the participant meet the AST, ALT, or bilirubin levels specified above prior to the day of the first dose of IMP, or (for Module 2 Part D) prior to randomisation.
3. All Modules: Other evidence of impaired hepatic synthesis function
4. All Modules: Any other malignancy not meeting inclusion criterion #10 (Module 1 Parts A, B, and C and Module 2 Part A and B), or inclusion criteria #13, 16 or 20 (Module 2 Part C or D),or inclusion criteria #25 (Module 2 Part D) which has been active or treated with systemic treatments or radiotherapy (± surgery) in the past 3 years. Localised (T1N0M0) tumours treated solely with curative surgical resection e.g. cervical intraepithelial neoplasia and, non-melanoma skin cancer are allowed.
5. All Modules: Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: a. Absolute neutrophil count (ANC) < 1.5 × 109/L. b. Platelet count < 100 × 109/L (<60 x 109/L for patients with HCC). c. Haemoglobin < 90 g/L.
6. All Modules: Any prior history of persistent (> 4 weeks) severe pancytopenia due to previous therapy rather than to disease (ANC < 0.5 × 109/L or platelets < 50 × 109/L).
7. All Modules: Cardiac dysfunction (defined as myocardial infarction within the last 6 months, New York Heart Association Class II/III/IV heart failure, unstable angina, unstable cardiac arrhythmias, or known left ventricular ejection fraction < 55%) or other clinically significant cardiac pathology likely to impair the participants ability to participate in the study. Participants with low normal LVEF (50-55%) are eligible if there is no evidence of significant cardiomyopathy or valvular disease on echo (or other imaging) and no significant clinical symptoms of heart failure.
8. All Modules: Mean QTcF > 450 ms for males or > 470 ms for females at both screening and prior to the first dose of IMP (on the day of first dose administration) (the mean of triplicate measurements [within 10 minutes with each reading separated by 1-5 minutes] will be used to determine eligibility). For Module 2 Part D participants, mean QTcF > 450 ms for males or > 470 ms for females is required at screening
9. All Modules: Any clinically important abnormalities in rhythm, conduction, or morphology on resting ECG (e.g., complete left bundle branch block, third degree heart block). Controlled atrial fibrillation is permitted.
10. All Modules: Any factor that in the Investigator’s opinion increases the risk of QTc prolongation or arrythmic events.
11. All Modules: In the opinion of the Investigator, unlikely to comply with study procedures, restrictions, or requirements.
12. All Modules: Participant has received an organ transplant.
13. All Modules: A history of haemolytic anaemia or marrow aplasia
14. All Modules: Has received a live virus vaccination within 28 days or less of planned treatment start. Note: seasonal flu or COVID vaccines that do not contain live virus are permitted
15. All Modules: History of Grade 3 or 4 pneumonitis or interstitial lung disease within the last 5 years, or other clinically significant pulmonary pathology likely to impair ability to participate in the study.
16. All Modules: Any unresolved toxicity (except alopecia) from prior therapy of ≥ CTCAE Grade 1, prior to the day of the first dose of IMP, or (for Module 2 Part D) prior to randomisation. Participants with Grade 2 toxicity that is not clinically significant (e.g., alopecia, vitiligo), or that is deemed stable or irreversible (e.g., peripheral neuropathy) can be enrolled.
17. Module 2 all Parts and Module 1A Crossover Participants Only: Has discontinued a prior checkpoint inhibitor due to toxicity.
18. Module 2 all Parts and Module 1A Crossover Participants Only: Hypersensitivity to cemiplimab or any of its excipients or contraindicated to cemiplimab per approved local labelling.
19. All Modules: Active or documented history of autoimmune disease (within 2 years) requiring systemic immunosuppressive therapy, or participant is immunocompromised for any other reason (as determined by the Investigator).
20. All Modules: Spinal cord compression or brain metastases, unless asymptomatic, stable, and not requiring steroids for at least 4 weeks before the day of the first dose of IMP, or (for Module 2 Part D) prior to randomisation (if stable and requiring no intervention, the participant can be enrolled in the study).
21. All Modules: Uncontrolled seizures
22. All Modules: Active infection requiring therapy within 14 days prior to the day of first dose of IMP, or (for Module 2 Part D) prior to randomisation.
23. All Modules: Known active hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection. Note: participants with prior hepatitis B or C infection which has been adequately treated (and/or is controlled) are eligible for study participation.
24. All Modules: Severe or uncontrolled medical condition (e.g., severe chronic obstructive pulmonary disease, severe Parkinson’s disease, active inflammatory bowel disease) or psychiatric condition.
25. All Modules: Active bleeding diatheses
26. Module 2 all Parts and Module 1A Crossover Participants Only: Has experienced ≥ Grade 2 immune-mediated AE on this study (applies to crossover participants only).
27. All Modules: Participant is breastfeeding or pregnant.
28. All Modules: Receipt of licenced or unlicenced cytotoxic, noncytotoxic or small molecule therapy for the malignancy within 28 days or 5 half-lives, whichever is shorter, prior to the day of first dose of IMP, or (for Module 2 Part D) prior to randomisation. Note: CPI therapy is permitted within any timeframe
29. All Modules: Receipt of oral corticosteroids (at a dose > 10 mg prednisone/day or equivalent) within 14 days prior to the day of the first dose of IMP, or (for Module 2 Part D) prior to randomisation (except for subjects receiving corticosteroids for adrenal insufficiency).
30. All Modules: Receipt of St John’s Wort within 21 days prior to the day of the first dose of IMP or of another concomitant medication, herbal supplement, or food that is a strong inhibitor or inducer of CYP3A4 enzymes (Section 23.5) within 14 days prior to the day of the first dose of IMP, or (for Module 2 Part D) prior to randomisation.
31. All Modules: Receipt of a blood transfusion (blood or blood products) within 7 days prior to the day of the first dose of IMP, or (for Module 2 Part D) prior to randomisation.
32. All Modules: Impaired hepatic or renal function as demonstrated by any of the following laboratory values: a. Albumin < 28 g/L. b. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × the upper limit of normal (ULN) (> 5.0 × ULN for participants with HCC or liver metastases). c. Total bilirubin > 1.5 × ULN (> 2.0 x ULN for participants with HCC, for participants with Gilbert’s syndrome, ULN is considered to be 2.9 mg/dL). d. Serum creatinine > 1.5 × ULN.
33. Module 2 Part D – pMMR/MSS CRC dose optimisation cohort: Participants with unresectable pMMR/MSS CRC may not have purely peritoneal disease.
34. Module 2 Part D – pMMR/MSS CRC dose optimisation cohort: Participants with unresectable pMMR/MSS CRC may not have had prior CPI / immunotherapy.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Incidence, type and severity of treatment-emergent and treatment-related adverse events (AEs)
2. Incidence and nature of DLTs or events meeting the DLT criteria
3. Comparative efficacy will be evaluated using the change in dimension over time of RECIST Target Lesions from baseline and on-study scans recorded at weeks 8 and 16.

Secondary endpoints 8

1. The MTD will be determined by the incidence of DLTs according to the MTD evaluation process.
2. The RP2D will be determined based on the safety, tolerability, PK, PDc and preliminary efficacy data of GRWD5769. The RP2D will not exceed the MTD.
3. Pharmacokinetic parameters to be evaluated (where possible) include (but are not limited to): • Trough concentrations • Maximum observed concentration (Cmax) • Time to Cmax (Tmax) • Trough concentrations • Area under the concentration-time curve (AUC last) • Half-life (t1/2) • Oral clearance (CL/F) • Apparent volume of distribution after oral administration (Vz/F)
4. RECIST 1.1 or iRECIST defined tumour response, including the frequency, quality and durability of response per RECIST 1.1 or iRECIST criteria. Specific endpoints include (but are not limited to): o Tumour size o Objective response rate (ORR) o Disease control rate (DCR) o Rate of participants with stable disease (stable disease rate [SDR]), defined as the proportion of participants with stable disease of at least 16 weeks per RECIST 1.1 or iRECIST o Time to response (TTR) - please see protocol
5. Change from baseline in disease-specific tumour markers (e.g. CA-125 for ovarian cancer, PSA for prostate cancer)
6. The MBAD is defined as the dose that achieves one of the following: a. Average total daily plasma (Cssave) of 3899 ng/mL b. A partial or complete RECIST 1.1 or iRECIST assessed response in at least one participant c. A clinically significant reduction (in the opinion of the safety review committee [SRC]), compared to baseline, in a tumour specific marker measured in at least one participant
7. Safety and tolerability endpoints include: • Incidence, type and severity of treatment-emergent and treatment-related adverse events (AEs) • Incidence and nature of events meeting the DLT criteria
8. Overall survival (Module 2 Part C and Module 2 Part D only)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Grey Wolf Therapeutics Limited

Sponsor organisation

Grey Wolf Therapeutics Limited

Address

99 Park Drive, Milton Milton

City

Abingdon

Postcode

OX14 4RY

Country

United Kingdom

Scientific contact point

Organisation

Grey Wolf Therapeutics Limited

Contact name

Grey Wolf

Public contact point

Organisation

Grey Wolf Therapeutics Limited

Contact name

Grey Wolf

Third parties 6

Locations

2 EU/EEA countries · 16 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 28 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

13 submissions — initial application plus substantial / non-substantial modifications