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Trial registered on ANZCTR


Registration number
ACTRN12623000108617
Ethics application status
Approved
Date submitted
9/11/2022
Date registered
31/01/2023
Date last updated
31/03/2023
Date data sharing statement initially provided
31/01/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A clinical trial to determine the safety and tolerability of GRWD5769 in patients with solid malignancies.
Scientific title
A modular, multi-part, multi-arm, open-label, Phase I/II Study to evaluate the safety and tolerability of GRWD5769 in patients with solid malignancies - Module 1.
Secondary ID [1] 307935 0
GRWD5769-ST-01
Universal Trial Number (UTN)
Trial acronym
EMITT-1 (ERAP Mediated Immunopeptidome Targeting Trial – 1)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced solid malignancies 327586 0
Condition category
Condition code
Cancer 325152 325152 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Module 1 aims to identify the minimum biologically active dose (MBAD),
maximum tolerated dose (MTD)/maximum feasible dose (MFD), and
recommended Phase 2 dose (RP2D) of GRWD5769 when administered as a
monotherapy in participants with advanced solid tumours. Module 1 will
initially include 4 separate parts (Parts A, B, C and D) as described below:

Part A: Part A is an open label, dose escalation part using a standard 3 + 3
design to determine the MTD/MFD and MBAD of GRWD5769 when
administered as a monotherapy. Up to 6 dose levels are planned to be
evaluated in Part A (further information is included below).

Part B (optional): Dose level cohorts which are at or above the MBAD may be
expanded to include up to an additional 12 participants for further evaluation
of the safety, tolerability, PK and PDc of GRWD5769.

Part C (optional): Part C may commence following the identification of at least
3 biologically active doses from Part A. In this study part, a single cohort of up
to 12 evaluable participants will be enrolled to evaluate safety, tolerability,
pharmacokinetic (PK) and pharmacodynamic (PDc) parameters following
intra-patient dose escalation of up to 3 dose levels of GRWD5769.

Part D (optional): The study may be expanded to evaluate GRWD5769 at the RP2D in up
to 3 subsets of participants with solid tumours (up to 30 participants per arm),
with subsets to be defined based on emerging data from Module 1 Part A, and
Part B. Module 1 Part D may commence following the identification of the GRWD5769 monotherapy RPD2.

In Module 1A, GRWD5769 capsules will be administered orally, twice daily (BID) on Days 1-14 of each 21-day treatment cycle. Cohort 1 will take 25mg twice daily. The dosing interval and dose level will be confirmed for each cohort by the Safety Review Committee, based upon emerging data from the preceding cohort(s). Additional dose levels may not exceed a doubling (total daily dose) of the highest previously evaluated dose level. The indicative GRWD5769 Monotherapy dose escalation scheme is as follows:
- GRWD5769 dose level of 25 mg; dosing frequency BID; 3-6 participants
- GRWD5769 dose level of 50 mg; dosing frequency to be determined; 3-6 participants
- GRWD5769 dose level of 100 mg; dosing frequency to be determined; 3-6 participants
- GRWD5769 dose level of 200 mg; dosing frequency to be determined; 3-6 participants
- GRWD5769 dose level of 400 mg; dosing frequency to be determined; 3-6 participants
- GRWD5769 dose level of 600 mg; dosing frequency to be determined; 3-6 participants

For each cohort, an initial single dose of GRWD5769 will be administered on Day 1, of Cycle 0, followed by a minimum 24-hour treatment free period, then twice daily dosing will commence.

In each study part, participants will continue to receive study medication until they withdraw their informed consent or are withdrawn from the study.

As described above, any participant who has completed 12 months on study and is still receiving clinical benefit from treatment with GRWD5769 may continue to receive GRWD5769 in a safety extension phase.

Compliance with IMP dosing will be monitored and recorded. Where dosing occurs in the clinic, the date and time of IMP dosing will be recorded by site staff. For any at-home dosing of GRWD5769, participants will record the date and time of each administration in a participant diary.

Participants who have completed 12 months on study may enter a safety extension phase where they may continue to receive GRWD5769 until evidence of disease progression.

Participants will have an end of treatment visit within 7 days of cessation of therapy. Reasons for withdrawal of study therapy regardless of length of time on study include:
• Disease progression as defined by iRECIST or unequivocal clinical progression as determined by the investigator
• Unacceptable toxicity, defined as:
o Occurrence of a DLT within the first cycle of treatment;
o Occurrence of an AE that is related to treatment with the study drug which compromises the participant’s ability to continue; or
o Persistent AE requiring a delay of therapy for more than 3 weeks (21 days)
• Intercurrent illness or interruption of therapy that requires a delay of therapy for more than 3 weeks (21 days)
• Participant chooses to withdraw from the study
• Any other reason, in the opinion of the PI, that renders the participant no longer appropriate for study continuation.

A final follow-up visit approximately 21 days (+ 7 days) post-last dose of GRWD5769.
Intervention code [1] 324393 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 332491 0
Safety and tolerability as assessed by incidence, type and severity of adverse events, graded in accordance with the Common Terminology Criteria for Adverse Events.

Adverse events of special interest (AESIs) include any suspected or confirmed cytokine release syndrome event, or any greater than or equal to Grade 3 immune-related AE determined to be at least probably or possibly related to IMP (GRWD5769).

AESIs will be captured as part of the standard AE reporting and extracted from all AEs collected when analysing data. No separate reporting mechanisms by the site, or data capture mechanisms for AESIs are required.

The PI (or medically qualified designee) will make an assessment of severity for each AE and SAE reported during the study. The assessment will be based on the PI’s clinical judgement. The severity of each event will be graded using the most current version of NCI-CTCAE (Version 5) 5-point scale

The Investigator will use clinical judgment to determine whether or not the AE/SAE is causally related to the study drug. Alternative causes, such as natural history of the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of the event to the study drug will be considered and investigated. The Investigator will also consult the IB (for GRWD5769) or CMI in the determination of his/her assessment.

The causal relationship of the study drug to an AE will be rated according to the following 5-point scale:
• Unrelated: Clearly and incontrovertibly due only to extraneous causes, and does not meet criteria listed under unlikely, possible or probable;
• Unlikely: Does not follow a reasonable temporal sequence from administration; may have been produced by the participant’s clinical state or by environmental factors or other therapies administered;
• Possibly: Follows a reasonable temporal sequence from administration; may have been produced by the participant’s clinical state or by environmental factors or other therapies administered;
• Probably: Clear temporal association with improvement on cessation of study drug or reduction in dose. Reappears upon re-challenge or follows a known pattern of response to the study drug;
• Definitely: An AE that cannot be reasonably explained by an alternative explanation, e.g., concomitant drug(s), concomitant disease(s). The relationship in time is very suggestive.
Timepoint [1] 332491 0
Adverse events are observed and recorded at every visit (during any time of the visit and not specifically in relation to IMP dosing) for the duration of treatment, and up to 21 days post cessation of GRWD5769 therapy.
Primary outcome [2] 332723 0
Safety and tolerability as assessed by incidence of dose limiting toxicities (DLTs).

A DLT is defined as any of the following that occur up to Day 21 in Cycle 1
- Grade 3 or 4 neutropenia (blood test result)
- Grade 3 thrombocytopenia (blood test result)
- Cytokine release syndrome Grade 3 or greater (blood test result)
- Any other confirmed haematological toxicity Grade 4 or greater (blood test result)
- Non haematological laboratory abnormalities Grade 3 or greater (blood test result)
- QTcF prolongation on electrocardiogram Grade 3 or greater (ECG finding)
Timepoint [2] 332723 0
From Cycle 0 Day 1 through to Cycle 1 Day 21.
Primary outcome [3] 332724 0
Safety and tolerability as assessed by changes from baseline in:
- Vital signs (pulse rate, temperature, systolic and diastolic blood pressure, respiration rate) measured as per site standard procedures.
Timepoint [3] 332724 0
Assessed at every scheduled visit for the duration of the study. Where vital signs assessments are scheduled on a dosing day, assessments should be measured within 90 minutes prior to morning dose administration. Additional measurements should also be collected as follows:
• C0 and C1D1: 1 hour and 6 hours post dose
• C2D1, and D1 of subsequent even numbered cycles (e.g. C4D1, C6D1, C8D1, etc. until end of treatment): 1 hour post dose
• Safety extension visit every 6 weeks if continuing treatment beyond 12 months, until disease progression.
• End of treatment visit within 7 days of cessation of therapy.
• Follow up visit 21 days post last dose
Secondary outcome [1] 413719 0
To characterise the plasma PK of GRWD5769 monotherapy, following single dose administration. 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 (AUC0-t)
• Half-life (t1/2)
• Oral clearance (CL/F)
• Absorption-dependent apparent volume of distribution in steady state (Vss/F)
Timepoint [1] 413719 0
Cycle 0: pre-dose, and 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h post dose.
Secondary outcome [2] 413720 0
Evaluate plasma accumulation of GRWD5769, following multiple (twice daily) dose administration.
Timepoint [2] 413720 0
Cycle 1: Day 1 and Day 14 pre-dose, and 1, 2, 4, 6, and 8 hours post morning dose, and 1, 2, 4, and 6 to 8 hours post evening dose
Cycle 1: Day 8 pre-dose
Cycle 2 onwards: Day 1 pre-dose (until evidence of disease progression or unacceptable toxicities).
Secondary outcome [3] 413725 0
Preliminary efficacy of GRWD5769 when administered as monotherapy as determined by tumour imaging (CT/MRI) and analysis of response per immune response evaluation criteria in solid tumours (iRECIST v1.1).
Timepoint [3] 413725 0
Imaging assessments will be performed during Screening, and every 8 weeks (plus or minus 1 week) after Cycle 1 Day 1 until disease progression.
Secondary outcome [4] 414524 0
Safety and tolerability as assessed by changes from baseline in:
- Clinical laboratory parameters in blood (haematology, serum chemistry, coagulation) and urine
Timepoint [4] 414524 0
Samples to be collected prior to dosing at the following visits:
Screening (Day -28 to Day 0)
Cycle 0 Day 1
Cycle 1: Days 1, 8 and 14
Cycle 2 onwards: Days 1 and 14
Safety extension visit every 6 weeks if continuing treatment beyond 12 months, until disease progression.
End of treatment visit within 7 days of cessation of therapy.
Follow up visit 21 days post last dose
Secondary outcome [5] 414525 0
Safety and tolerability as assessed by changes from baseline in:
- ECG parameters (HR, PR interval, QT interval, PR interval, RR interval, QRS duration, and QTcF)
Timepoint [5] 414525 0
Prior to first dose on Cycle 0 Day 1, and at the following visits:
Cycle 1: Days 1, 8 and 14
Cycle 2 onwards until end of treatment: Day 1
End of treatment visit within 7 days of cessation of therapy.
Secondary outcome [6] 414526 0
Safety and tolerability as assessed by changes from baseline in:
- ECOG performance status
Timepoint [6] 414526 0
ECOG performance status assessed prior to dosing at the following visits:
Screening (once during period Day -28 to Day 0)
Cycle 0: Day 1
Cycle 2 onwards until end of treatment: Day 1
End of treatment visit within 7 days of cessation of therapy.
Follow up visit 21 days post last dose
Safety extension visit every 6 weeks
Secondary outcome [7] 414527 0
Safety and tolerability as assessed by changes from baseline in:
- Body weight measured as per site standard procedures
Timepoint [7] 414527 0
Body weight assessed prior to dosing at the following visits:
Screening (Day -28 to Day 0): once
Cycle 0: Day 1
Cycle 2 onwards until end of treatment: Day 1
End of treatment visit within 7 days of cessation of therapy.
Follow up visit 21 days post last dose
Safety extension visit every 6 weeks

Eligibility
Key inclusion criteria
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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features

Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
20/03/2023
Actual
21/03/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
36
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC
Recruitment hospital [1] 24353 0
Southern Oncology Clinical Research Unit - Bedford Park
Recruitment postcode(s) [1] 39923 0
5042 - Bedford Park

Funding & Sponsors
Funding source category [1] 312204 0
Commercial sector/Industry
Name [1] 312204 0
Grey Wolf Therapeutics Pty Ltd
Country [1] 312204 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Grey Wolf Therapeutics Pty Ltd
Address
Bio101
Suite 201/697 Burke Road
Camberwell, VIC 3124
Country
Australia
Secondary sponsor category [1] 313730 0
None
Name [1] 313730 0
NA
Address [1] 313730 0
NA
Country [1] 313730 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311587 0
Bellberry HREC
Ethics committee address [1] 311587 0
123 Glen Osmond Road Eastwood Adelaide
South Australia 5063
Ethics committee country [1] 311587 0
Australia
Date submitted for ethics approval [1] 311587 0
09/11/2022
Approval date [1] 311587 0
16/01/2023
Ethics approval number [1] 311587 0
2022-11-1223

Summary
Brief summary
This study aims to assess a new cancer drug, GRWD5769, in patients with advanced cancer.

Who is it for?
You may be eligible to join this study if you are aged 18 years or older, have a cytologically or histologically confirmed locally advanced or metastatic solid malignancy not considered for further treatment, and have progressive disease after treatment with other agents.

Study details
All participants will receive treatment with GRWD5769. The drug will be administered as an oral capsule, initially as a single dose followed by a minimum 24-hour treatment free period, during which blood samples will be taken. After this, participants will take the study drug twice daily on days 1-14 of each 21-day treatment cycle. Treatment will continue until participants withdraw from the study or their disease progresses.

During the treatment period, participants will undergo study visit for screening, an initial confinement period commencing up to 2 days prior to the first dose until Day 2 of Cycle 1 (minimum of 2 nights), Day 8 of Cycle 1, a confinement period during Day 14 and Day 15 of Cycle 1 and from Cycle 2 onwards, at Days 1 and Day 14 so that safety assessments can be conducted. Participants will also undergo imaging every 56 days for the duration of the study to assess for their response to treatment.

It is hoped that this study will show that GRWD5769 is safe, tolerable, and effective for the treatment of advanced solid cancers. This study will also help to define the dose of GRWD5769 that may be used for treatment of similar individuals in future.


Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 121622 0
Dr Ganessan Kichenadasse
Address 121622 0
Southern Oncology Clinical Research Unit
Level 3
Mark Oliphant Building
5 Laffer Drive, Bedford Park
South Australia, 5042
Country 121622 0
Australia
Phone 121622 0
+61 491 679 039
Fax 121622 0
Email 121622 0
ganessan.kichenadasse@socru.org.au
Contact person for public queries
Name 121623 0
Jessica Sette
Address 121623 0
Grey Wolf Therapeutics Pty Ltd
Bio101
Suite 201/697 Burke Road
Camberwell, VIC 3124
Country 121623 0
Australia
Phone 121623 0
+61 8 6186 1875
Fax 121623 0
Email 121623 0
enquiries-au@gwt.bio
Contact person for scientific queries
Name 121624 0
Paul Wabnitz
Address 121624 0
cPHARMA
307 Unley Rd, Malvern SA 5061, Australia
Country 121624 0
Australia
Phone 121624 0
+61 448 665 638
Fax 121624 0
Email 121624 0
paul.wabnitz@clinPHARMA.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.