Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623001077651
Ethics application status
Approved
Date submitted
4/09/2023
Date registered
10/10/2023
Date last updated
10/10/2023
Date data sharing statement initially provided
10/10/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A clinical trial to determine the safety and tolerability of GRWD5769 in combination with anticancer treatments 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 Alone and in Combination with Anticancer Treatments in Patients with Solid Malignancies - Module 2.
Secondary ID [1] 309073 0
GRWD5769-ST-01 Module 2
Universal Trial Number (UTN)
Trial acronym
EMITT-1 (ERAP Mediated Immunopeptidome Targeting Trial – 1)
Linked study record
This is a sub-study of ACTRN12623000108617. Considered an additional module; Module 2. Refer to secondary ID.

Health condition
Health condition(s) or problem(s) studied:
Advanced solid malignancies 329133 0
Condition category
Condition code
Cancer 326111 326111 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Module 2 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 used in combination with cemiplimab in participants with advanced solid tumours. Module 2 may commence following identification of the GRWD5769 monotherapy MBAD in Module 1, Part A (ACTRN12623000108617; this will be the starting dose level for Module 2). Module 2 will initially include 3 separate parts (Parts A, B and C) as described below:

Part A: Part A is an open label, dose escalation part to determine the MTD/MFD of GRWD5769 when administered in combination with cemiplimab-rwlc 350 mg. Up to 6 dose levels are planned to be evaluated in Part A (in up to 6 cohorts) and dose escalation at each cohort is planned at 25mg, 50mg, 100mg, 200mg, 400mg and 800mg BID. The number of participants expected in Part A is up to 36.

Part B (optional): Module 2 Part B may commence following the identification of
the GRWD5769 combination therapy RP2D. 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, pharmacokinetic (PK) and pharmacodynamic (PDc) of GRWD5769 in combination with cemiplimab-rwlc 350 mg.

Part C: The study may be expanded to evaluate GRWD5769 at the RP2D in
combination with cemiplimab-rwlc 350 mg 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 2 Part A.

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. For each dose level cohort in Module 2 GRWD5769 capsules will be administered orally, twice daily (BID) on Days 1-14 of each 21-day treatment cycle, and cemiplimab-rwlc will be administered as an intravenous infusion of 350 mg over 30 minutes, every 3 weeks (Q3W), on Day 1 of each Cycle 1 onwards. Each dose of cemiplimab-rwlc will be administered in the clinic, under the supervision of site staff.

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

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 and cemiplimab-rwlc 350mg until evidence of disease progression.

Participants will have an end of treatment visit within 7 days of cessation of therapy and again for a final follow up visit 30 days following cessation of therapy. Participants enrolled in Module 2 will have a telephone call at 90 days following last dose of cemplimab-rwlc 350mg.

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.
Intervention code [1] 325540 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 334010 0
Safety and tolerability of GRWD5769 when administered in combination with cemiplimab-rwlc 350 mg 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] 334010 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] 334011 0
Safety and tolerability of GRWD5769 when administered in combination with cemiplimab-rwlc 350 mg 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] 334011 0
From Cycle 0 Day 1 through to Cycle 1 Day 21.
Primary outcome [3] 334012 0
Safety and tolerability of GRWD5769 when administered in combination with cemiplimab-rwlc 350 mg 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] 334012 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:
• Cycle 0 and Cycle 1 Day 1: 1 hour and 6 hours post dose
• Cycle 2 Day 1, and Day 1 of subsequent even numbered cycles (e.g. Cycle 4 Day 1, Cycle 6 Day 1, Cycle 8 Day 1, 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] 419073 0
To evaluate plasma accumulation of GRWD5769 when administered in
combination with cemiplimab-rwlc 350mg.

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] 419073 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 3: Day 14 2hr and 6hr post dose
Cycle 4 onwards: Day 1 pre-dose (until evidence of disease progression or unacceptable toxicities).
Secondary outcome [2] 419074 0
Preliminary efficacy of GRWD5769 when administered in combination with cemiplimab-rwlc 350mg as determined by tumour imaging (CT/MRI) and analysis of response per immune response evaluation criteria in solid tumours (iRECIST v1.1).
Timepoint [2] 419074 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 [3] 419075 0
Safety and tolerability as assessed by changes from baseline in:
- Clinical laboratory parameters in blood and urine (haematology, serum chemistry, coagulation, thyroid function tests).
Timepoint [3] 419075 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 [4] 419076 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 [4] 419076 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 [5] 419077 0
Safety and tolerability as assessed by changes from baseline in:
- ECOG performance status
Timepoint [5] 419077 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 [6] 419078 0
Safety and tolerability as assessed by changes from baseline in:
- Body weight measured as per site standard procedures
Timepoint [6] 419078 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 2A specific
1. Participant has cytologically or histologically confirmed locally advanced or metastatic solid malignancy and has received at least one line of prior therapy or has no further (or has refused) standard of care options.
2. Participant has measurable disease per RECIST 1.1/iRECIST.
Module 2B 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 2C specific
Additional selection criteria for Module 2 Part C will be described in a
future protocol amendment.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
All Module 2
1. Prior therapy with an ERAP1 inhibitor, within any timeframe prior to the first dose of
study drug at Cycle 0, Day 1.
2. Any other malignancy not meeting inclusion criterion 1 which has been active or treated
within the past 3 years, with the exception of cervical intraepithelial neoplasia and nonmelanoma skin cancer.
3. Any unresolved toxicity (except alopecia) from prior therapy of greater than or equal to CTCAE Grade 3, prior to the first dose of IMP at Cycle 0, Day 1.
4. 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).
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 participant can be enrolled in the study).
6. Uncontrolled seizures
7. Active infection requiring intravenous antibiotic, antifungal, or antiviral medication or hospital admission 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. Participant has received an organ transplant
11. Known hepatitis B, hepatitis C, Epstein-Barr virus (EBV) or human immunodeficiency
virus infection (HIV).
12. Participant is breastfeeding or pregnant
13. Receipt of licensed or unlicensed cytotoxic, non-cytotoxic or small molecule therapy for the malignancy within 28 days or 5 half-lives,
whichever is shorter, prior to the first dose of IMP at Cycle 0, Day 1
14. Receipt of oral corticosteroids (at a dose greater than 10 mg prednisone/day or equivalent) within 14 days prior to the first dose of IMP (except for subjects receiving corticosteroids for adrenal insufficiency) at Cycle 0, Day 1
15. Receipt of St John’s Wort within 21 days prior to 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 prior to the first dose of IMP at Cycle
0, Day 1
16. Receipt of a blood transfusion (blood or blood products) within 14 days prior to the first
dose of IMP at Cycle 0, Day 1
17. Impaired hepatic or renal function as demonstrated by any of the following laboratory
values:
a. Albumin less than 30 g/L.
b. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 2.5 times the
upper limit of normal (ULN) (greater than 5.0 times ULN for participants with liver metastases).
c. Total bilirubin greater than 1.5 times ULN (for participants with gilbert's syndrome, ULN is considered to be 2.9 mg per ml)
d. Serum creatinine greater than 1.5 times ULN.
18. Liver function deteriorating in a manner that would likely make the participant meet the
AST, ALT, or bilirubin levels specified above prior to the first dose of IMP at Cycle 0,
Day 1.
19. Other evidence of impaired hepatic synthesis function.
20. 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 109/L.
b. Platelet count less than 100 times 109/L.
c. Haemoglobin less than 90 g/L.
21. Any prior history of persistent (greater than 4 weeks) severe pancytopenia due to previous therapy
rather than to disease (ANC less than 0.5 times 109/L or platelets less than 50 times 109/L).
22. 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 less than 55%).
23. Mean QTcF greater than 450 ms for males or greater than 470 ms for females at both Screening and prior to the first dose of IMP at Cycle 0, Day 1 (the mean of triplicate measurements [within 10 minutes with each reading separated by 1-5 minutes] will be used to determine eligibility).
24. 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.
25. Any factor that in the investigator's opinion increases the risk of QTc prolongation or of arrhythmic events
26. In the opinion of the Investigator, unlikely to comply with study procedures, restrictions,
or requirements.
27. A history of haemolytic anaemia or marrow aplasia.
28. 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.
29. History of Grade 3 or 4 pneumonitis or interstitial lung disease within the last 5 years
30. Any prior Grade 3 or 4 immune mediated toxicity due to checkpoint inhibitors
31. Hypersensitivity to cemiplimab or any of its excipients, or contraindicated to cemiplimab per approved local labelling

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
Not yet recruiting
Date of first participant enrolment
Anticipated
1/12/2023
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
36
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC
Recruitment hospital [1] 24930 0
Southern Oncology Clinical Research Unit - Bedford Park
Recruitment hospital [2] 24931 0
The Alfred - Melbourne
Recruitment hospital [3] 24932 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [4] 25493 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 40582 0
5042 - Bedford Park
Recruitment postcode(s) [2] 40583 0
3004 - Melbourne
Recruitment postcode(s) [3] 40584 0
2010 - Darlinghurst
Recruitment postcode(s) [4] 41304 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 313279 0
Commercial sector/Industry
Name [1] 313279 0
Grey Wolf Therapeutics Pty Ltd
Country [1] 313279 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] 315016 0
None
Name [1] 315016 0
NA
Address [1] 315016 0
NA
Country [1] 315016 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312508 0
The Alfred Hospital Ethics Committee
Ethics committee address [1] 312508 0
Ethics committee country [1] 312508 0
Australia
Date submitted for ethics approval [1] 312508 0
01/09/2023
Approval date [1] 312508 0
21/09/2023
Ethics approval number [1] 312508 0
Ethics committee name [2] 313235 0
Bellberry
Ethics committee address [2] 313235 0
Ethics committee country [2] 313235 0
Australia
Date submitted for ethics approval [2] 313235 0
31/08/2023
Approval date [2] 313235 0
Ethics approval number [2] 313235 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 124910 0
Dr Ganessan Kichenadasse
Address 124910 0
Southern Oncology Clinical Research Unit Level 3 Mark Oliphant Building 5 Laffer Drive, Bedford Park, South Australia, 5042
Country 124910 0
Australia
Phone 124910 0
+61 491 679 039
Fax 124910 0
Email 124910 0
[email protected]
Contact person for public queries
Name 124911 0
Mara Giovanetti
Address 124911 0
Grey Wolf Therapeutics Pty Ltd, Bio 101 Suite 201/697 Burke Road Camberwell, VIC 3124
Country 124911 0
Australia
Phone 124911 0
+61 8 6186 1875
Fax 124911 0
Email 124911 0
[email protected]
Contact person for scientific queries
Name 124912 0
Paul Wabnitz
Address 124912 0
cPHARMA, 307 Unley Rd, Malvern SA 5061, Australia
Country 124912 0
Australia
Phone 124912 0
+61 448 665 638
Fax 124912 0
Email 124912 0
[email protected]

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

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No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.