Inclusion
Module 1 (Parts A and C) Specific:
1. Participant has cytologically or histologically confirmed locally advanced or metastatic
solid malignancy not considered appropriate for further standard treatment.
2. Participant has measurable disease per RECIST 1.1/iRECIST.
Module 1 (Part B) Specific:
1. Participant has cytologically or histologically confirmed locally advanced or metastatic
solid malignancy.
2. Participant has confirmed progressive disease after treatment with an anti-PD-1 or anti-
PD-L1 mAb, following a minimum treatment duration of 12 weeks (or at least 2 response evaluations).
3. 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.
Module 1 (Part D) Specific:
Additional selection criteria for Module 1 Part D will be described in a future protocol amendment.
All study Modules 1:
1. 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. An ECOG performance status of 0 or 1 with no deterioration over the previous 2 weeks.
3. Willing to permit access to stored historical tumour tissue and prior tumour radiological assessments and tumour biomarker data (if available).
4. Able to take oral medications and be willing to record daily adherence to the study drug.
5. Female patients must be of non-child-bearing potential i.e., surgically sterilized (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before the screening visit) or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause and a follicle-stimulating hormone (FSH) level consistent with postmenopausal status, per local laboratory guidelines), or, if of child-bearing 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
b. Must agree not to attempt to become pregnant
c. Must not donate ova from signing consent until at least 33 days (30 days plus a minimum of 5 half lives of GRWD5769) after the last dose of study drug
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 from signing the consent form until at least 33 days after the last dose of study drug.
6. Male patients must:
a. Agree not to donate sperm from the time of signing consent until at least 93 days (90 days plus a minimum of 5 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 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 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.
7. Estimated life expectancy of at least 3 months, in the opinion of the Principal Investigator.
8. Willing and able to comply with all scheduled visits, treatment plans, laboratory tests, and other study procedures.
Exclusion
All study Modules 1:
1. Prior therapy with an ERAP1 inhibitor, within any timeframe prior to the first dose of study drug.
2. Any other malignancy that does not meet the inclusion criterion for the patient to have a cytologically or histologically confirmed locally advanced or metastatic solid malignancy not considered appropriate for further standard treatment, which has been active or treated within the past 3 years, with the exception of cervical intraepithelial neoplasia and non-melanoma skin cancer
3. Any unresolved toxicity (except alopecia) from prior therapy of greater than or equal to CTCAE Grade 3
4. Active or documented history of autoimmune disease
5. Spinal cord compression or brain metastases, unless asymptomatic, stable, and not requiring steroids for at least 4 weeks before the first dose of IMP (if stable and requiring no intervention, the patient can be enrolled in the study).
6. Uncontrolled seizures
7. Active infection requiring systemic antibiotic, antifungal, or antiviral medication within 14 days prior to first dose of study drug
8. Severe or uncontrolled medical condition (e.g., severe chronic obstructive pulmonary disease, severe Parkinson’s disease, active inflammatory bowel disease) or psychiatric condition
9. Active bleeding diatheses
10. Patient has received a renal transplant
11. Active hepatitis B, hepatitis C, or human immunodeficiency virus infection.
12. Patient is breastfeeding or pregnant
13. Receipt of cytotoxic treatment for the malignancy within 28 days or 5 half-lives, whichever is longer, before the first dose of IMP
14. Receipt of noncytotoxic treatment for the malignancy (including biologics such as immune checkpoint inhibitors, antibodies, nanoparticles etc.) within 5 half-lives of the drug or 42 days (whichever is longer) before the first dose of study drug (exception: anti-PD-1 or anti-PD-L1 mAb therapy)
15. Receipt of corticosteroids (at a dose greater than 10 mg prednisone per day or equivalent) within 14 days before the first dose of IMP
16. Receipt of any small molecule IMP within 28 days or 5 half lives, whichever is longer, before the first dose of IMP
17. Receipt of St John’s Wort within 21 days before the first dose of IMP or of another concomitant medication, herbal supplement, or food that is a strong inhibitor or inducer of CYP3A4 enzymes within 14 days before the first dose of IMP
18. Receipt of a blood transfusion (blood or blood products) within 14 days before the first dose of IMP
19. Impaired hepatic or renal function as demonstrated by any of the following laboratory values:
a. Albumin less than 30 g per L.
b. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 2.5 times the the upper limit of normal (ULN) (greater than 5.0 times the ULN for patients with liver metastases).
c. Total bilirubin greater than 1.5 times the ULN.
d. Serum creatinine greater than 1.5 times the ULN.
20. Liver function deteriorating in a manner that would likely make the patient meet the AST, ALT, or bilirubin levels specified above at the time of the first dose of IMP.
21. Other evidence of impaired hepatic synthesis function.
22. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:
a. Absolute neutrophil count (ANC) less than 1.5 times 10 to the power of 9 per L.
b. Platelet count less than 100 times 10 to the power of 9 per L.
c. Haemoglobin less than 90 g per L.
23. Persistent (greater than 4 weeks) severe pancytopenia due to previous therapy rather than to disease (ANC less than 0.5 times 10 tot he power of 9 per L or platelets less than 50 times 10 to the power of 9 per L).
24. Cardiac dysfunction (defined as myocardial infarction within 6 months of study entry, New York Heart Association Class II, III, IV heart failure, unstable angina, unstable cardiac arrhythmias, or left ventricular ejection fraction less than 55%).
25. Mean QT interval corrected by Fridericia’s formula (QTcF) greater than 450 ms for males or greater than 470 ms for females at Screening and on Day 1, prior to the start of study treatment (the mean of triplicate measurements [within 10 minutes with each reading separated by 1 to 5 minutes] will be used to determine eligibility).
26. 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 (AF) is permitted.
27. Any factor that increases the risk of QTc prolongation or of arrhythmic events (e.g., heart failure, hypokalaemia, congenital long QT syndrome, immediate family history of long QT syndrome or unexplained sudden death under 40 years of age).
28. In the opinion of the Investigator, unlikely to comply with study procedures, restrictions, or requirements.
29. A history of haemolytic anaemia or marrow aplasia.
30. Has received a live-virus vaccination within 28 days or less of planned treatment start.