Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620001146987
Ethics application status
Approved
Date submitted
2/09/2020
Date registered
2/11/2020
Date last updated
23/02/2024
Date data sharing statement initially provided
2/11/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase I study of PMR-116 in Patients with Advanced Malignancies
Scientific title
Investigating the safety and tolerability of PMR-116 in Patients with Advanced Malignancies
Secondary ID [1] 302162 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced solid tumours 318815 0
Condition category
Condition code
Cancer 316828 316828 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
PMR-116 will be administered as an oral liquid contained within a pre-filed syringe at the dose defined by the protocol and the SRC. Participants will fast 2 hours prior to and 1 hour post each dose.

Part 1:
Dose Escalation - multiple ascending dose cohorts
PMR-116: will be self administered by the participant once every 7 days, with each cycle being 28 days. PMR-116 will be given at either 300mg, 600mg, 900mg, 1350mg and 1800mg per dose.

In this dose escalation phase individual dosing cohorts will be sequentially enrolled. The decision to escalate to the next dose level in this phase of the study will be made following evaluation of the safety, efficacy and pharmacodynamic data by the Safety Review Committee (SRC).


Dose Schedule Optimization – multiple dose levels with dose administration of 2-, 3- or 4-consecutive days
Following completion of the dose escalation phase, further optimization of the dose administration schedule with PMR-116 will be conducted. Oral PMR-116 will be administered with dosing schedules of 2days on/5 days off, 3 days on/4 days off or 4-days on/10 days off, with each cycle being 28 days.

The first two cohorts will be concurrently enrolled, at 400mg, 3 days on/5 days off and 600mg, 2 days/4 days off. Participants will be enrolled on a 1:1 basis between the two dosing regimens.

Following these two cohorts, the dose and the dosing schedule for future cohorts will be determined by the SRC following evaluation of the safety, efficacy and pharmacodynamic data. The total weekly dose level not exceed 1800mg/week.


Part 2: Dose Expansion – single dose cohort
Oral PMR-116 will be self administered at a dose and dose schedule determined by the SRC following the dose escalation and dose schedule optimisation phases of the study.

In all parts of the study, participants will be required to capture their dosing in a participant diary that will be reviewed by the clinical unit staff at scheduled site clinic visits and to return to the site their used dosing syringes.

Participants will continue to receive study drug until they are no longer considered to be achieving clinical benefit; they have unacceptable toxicity; or they withdraw informed consent.

Study participation consists of 28 day screening period, treatment period and an a End of Treatment visit will be conducted 30 days after the last dose of PMR-116. Attendance at the clinical unit will be dependent on the dosing schedule enrolled in, as described below:
• Dose Escalation, dosing every 7 days: . Cycle 1 Days 1, 2,8,15,22 and 23, Cycle 2 Days 1 and 15, and Day 1 of each subsequent cycle
• Dose Schedule Optimization, 2 days on/5 days off: Cycle 1 days 1, 2, 3, 8, 9, 15, 22, 23, 24, Cycle 2 days 1, 2, 15 and Day 1 of subsequent cycles.
• Dose Schedule Optimization, 3 days on/4 days off: Cycle 1 days 1, 2, 3, 4, 8, 9, 10, 15, 22, 23, 24, 25. Cycle 2 days 1, 2, 3, 15, 16 and Day 1 of subsequent cycles.
• Dose Schedule Optimization, 4 days on/10 days off: Cycle 1 days 1, 2, 3, 4, 5, 15, 16, 17, 18, 19. Cycle 2 days 1, 15 and Day 1 of subsequent cycles.

Participants may only take part in either the Dose Escalation, Dose Schedule Optimization or the Dose Expansion aspects of the study and, where enrolled into the Part 1-Dose Escalation / Dose Schedule Optimization phases, only one cohort.
Intervention code [1] 318463 0
Treatment: Drugs
Comparator / control treatment
No control group.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 324946 0
Safety and tolerability will be assessed by the participant reporting of adverse events via diary entry and during review by the clinical unit staff, dose limiting toxicities, clinical laboratory tests (Haematology, biochemistry, coagulation and urinalysis), physical examination, vital signs (systolic and diastolic blood pressures as measured by a sphygmomanometer, respiratory rate as assessed by the counting of breaths taken per minute,, pulse as measured by a heart rate monitor and body temperature as measured by a thermometer on the outside of the ear canal or forehead), 12-lead ECGs and Eastern Cooperative Oncology Group (ECOG) performance status. All data pertaining to safety will be captured in an electronic database
Timepoint [1] 324946 0
Participants attendance at the clinic will be dependent on the dosing schedule they are assigned, as described:
• Dose Escalation, dosing every 7 days: Cycle 1 Days 1, 2,8,15,22 and 23, Cycle 2 Days 1 and 15, and Day 1 of each subsequent cycle
• Dose Schedule Optimization, 2 days on/5 days off: Cycle 1 days 1, 2, 3, 8, 9, 15, 22, 23, 24, Cycle 2 days 1, 2, 15 and Day 1 of subsequent cycles.
• Dose Schedule Optimization, 3 days on/4 days off: Cycle 1 days 1, 2, 3, 4, 8, 9, 10, 15, 22, 23, 24, 25. Cycle 2 days 1, 2, 3, 15, 16 and Day 1 of subsequent cycles.
• Dose Schedule Optimization, 4 days on/10 days off: Cycle 1 days 1, 2, 3, 4, 5, 15, 16, 17, 18, 19. Cycle 2 days 1, 15 and Day 1 of subsequent cycles.

Participants will then return for follow up at an End of Study Visit 30 days after their last dose of PMR-116, prior to the completion of their study participation.

In the Dose escalation and Dose Schedule Optimization Phases, the Safety Review Committee will convene to review all available safety information to determine whether to proceed to the next dose level.

During the dose expansion phase, participants will attend the clinic dependent on the dosing schedule selected by the SRC for this phase of the study. Participants will return for follow up at an End of Study Visit prior to the completion of their study participation. This aspect of the study will also be overseen by a Safety Review Committee who will review available safety information on an ongoing basis.
Secondary outcome [1] 386280 0
The following pharmacokinetic parameters will be measured on plasma samples Cmax, Tmax, AUC 0-t, apparent terminal elimination half-life.
Timepoint [1] 386280 0
During the Dose Escalation Phase, PK samples will be collected: prior to dosing and at 0.5, 1, 2, 4, 8, and 10-12 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 22. A single sample for measurement of PK will be collected on Cycle 1 Days 2, 8, and 23 and Cycle 2 Day 1.
During the Dose Schedule Optimisation Phase, PK samples will be taken as described below:
• .2 days on/5 days off: C1D1 prior to dosing, 1, 2,4, 6 hours post dose. C1D2 pre-dose, then 1, 2, 4 hours post dose. Prior to dosing on C1d8, 15, 22 and 24. C1D22 additional PK samples collected at 1, 2 and 4 hours post dose.
• 3 days on/4 days off: C1D1 pre-dose, 1, 2, 4, 6 hours post dose. C1D2 pre-dose. C1D3 pre-dose, 1,2, 4hrs post dose. Pre-dose C1 Days 8. 15, 24 and 25. Additional PK samples collected on C1D22 at 1, 2, 4 hours post dose.
• 4 days on, 10 days off: C1D1 pre dose, 1, 2, 4, 6 hours post dose. C1 days 2 and 3 pre-dose. C1D4 pre-dose, 1, 2, 4 and 24hours post dose. C1D15 Pre dose, 1, 2, 4, 6, hours post dose. C1 days 16, 17, pre dose. C1D18 pre-dose, 1, 2, 4 and 24 hours post dose.
Secondary outcome [2] 386281 0
Preliminary anti-tumour activity of PMR-116 will be assessed by the frequency, quality and durability of response per RECIST 1.1. using CT or MRI imaging
Timepoint [2] 386281 0
Imaging assessments of tumours will be performed at screening and then every 8 weeks for the first 12 months of study participation and every 12 weeks thereafter from Cycle 1 Day 1 until completion of study participation per RECIST 1.1

Eligibility
Key inclusion criteria
• Ability to understand and be willing to sign an informed consent form.
• MYC positive, histopathologically confirmed, locally advanced or metastatic cancer (solid tumour) for which all available standard of care treatment options has been exhausted or refused and for which at least one lesion is measurable.
• Most recent chemotherapy treatment at least 3 weeks, or monoclonal antibody treatment at least 4 weeks, or allogeneic stem cell transplantation at least 24 weeks or radiation therapy at least 3 weeks prior to starting treatment with PMR-116.
• Males and females aged over 18 years
• Eastern Cooperative Oncology Group (ECOG) status of 0 to 1
• Adequate liver and renal function as evidenced by pathology test results
• No recent major surgery at least 4 weeks prior to starting treatment with PMR-116
• Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal.
• Males must be surgically sterile, abstinent, or if engaged in sexual relations with a woman of child-bearing potential, the participant and his partner must be surgically sterile or using an acceptable, highly effective contraceptive method from screening until study completion.
• Be willing to use protective measures against sun exposure and avoid the use of tanning salons and tanning beds
• Have an estimated life expectancy of at least 3 months.
• Dose Expansion only: Have a site of disease amenable to biopsy and be willing to undergo a biopsy prior to and during treatment with PMR-116
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Receiving any concurrent anti-cancer therapy
• Adverse Events from prior treatments which have not recovered to at least a mild (Grade 1) severity
• Symptomatic primary Central Nervous System (CNS) cancer or metastases unless the symptoms are stable with no CNS surgery or radiotherapy within 28 days prior to the first dose of PMR-116
• Any uncontrolled illness that would limit compliance with study requirements
• Any uncontrolled infection
• Known Human Immunodeficiency Virus (HIV) infection
• Active hepatitis B or hepatitis C infection
• Pregnant or breast feeding
• Unable to swallow oral medications
• Gastrointestinal conditions that could affect absorption of PMR-116
• Evidence of abnormal cardiac function
• Prior treatment with an RNA polymerase I inhibitor

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)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable-Open label
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
Safety/efficacy
Statistical methods / analysis
The sample size determination for dose escalation and dose schedule optimization is based on standard Phase I studies using an accelerated 3 + 3 design to enable determination of the MTD. A sample size of 15 patients for the dose expansion part of the study will provide an opportunity to identify early signs of promising clinical activity for subsequent formal Phase II studies that is compatible with an acceptable type II error.
Statistical analyses will be primarily descriptive; no formal hypothesis testing will be
conducted. Descriptive statistics will be provided for selected baseline, safety, PK, PD and
efficacy data by dose level and time point as appropriate.

Recruitment
Recruitment status
Stopped early
Data analysis
No data analysis planned
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
‘Stopped early - As the goals and objectives of PMR-116-001 Part 1 have been achieved, sponsor decision to terminate the remaining study cohorts’.
Date of first participant enrolment
Anticipated
11/11/2020
Actual
30/12/2020
Date of last participant enrolment
Anticipated
23/04/2024
Actual
5/07/2023
Date of last data collection
Anticipated
21/05/2024
Actual
22/01/2024
Sample size
Target
54
Accrual to date
Final
24
Recruitment in Australia
Recruitment state(s)
NSW,WA,VIC
Recruitment hospital [1] 17350 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [2] 17351 0
Linear Clinical Research - Nedlands
Recruitment hospital [3] 17352 0
Scientia Clinical Research - Randwick
Recruitment hospital [4] 17353 0
The Alfred - Melbourne
Recruitment postcode(s) [1] 31080 0
3000 - Melbourne
Recruitment postcode(s) [2] 31081 0
6009 - Nedlands
Recruitment postcode(s) [3] 31082 0
2031 - Randwick
Recruitment postcode(s) [4] 31083 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 306590 0
Commercial sector/Industry
Name [1] 306590 0
Pimera Australia Pty Ltd
Country [1] 306590 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Pimera Australia Pty Ltd
Address
58 Gipps Street, Collingwood, Victoria, 3066
Country
Australia
Secondary sponsor category [1] 307121 0
None
Name [1] 307121 0
Address [1] 307121 0
Country [1] 307121 0
Other collaborator category [1] 281440 0
Commercial sector/Industry
Name [1] 281440 0
Avance Clinical
Address [1] 281440 0
213 Glyndburn Road, Firle, South Australia, 5070
Country [1] 281440 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306772 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 306772 0
123 Glen Osmond Road, Eastwood, South Australia, 5066
Ethics committee country [1] 306772 0
Australia
Date submitted for ethics approval [1] 306772 0
09/09/2020
Approval date [1] 306772 0
27/10/2020
Ethics approval number [1] 306772 0
2020-09-856
Ethics committee name [2] 306774 0
Peter MacCallum Ethics Committee
Ethics committee address [2] 306774 0
305 Grattan Street
Melbourne, Victoria 3000
Ethics committee country [2] 306774 0
Australia
Date submitted for ethics approval [2] 306774 0
12/10/2020
Approval date [2] 306774 0
Ethics approval number [2] 306774 0

Summary
Brief summary
This is an open-label multiple ascending dose study to assess the safety and tolerability of PMR-116, a drug treatment for patients with advanced solid tumours of any cancer type.

Who is it for?
You may be eligible for this study if you are aged 18 years or older, have been diagnosed with a solid tumour of any cancer type, and you have previously failed treatment with other available therapies indicated for your cancer (including chemotherapy, surgery and radiation therapy).

Study details
This trial will be conducted across two parts. In the first study part (Dose escalation), up to six participants will receive multiple doses of PMR-116, to be taken at set times throughout a 28-day treatment cycle. All participants will have their vital signs checked (heart rate, blood pressure, temperature, etc), and will provide blood and urine samples for testing. If the drug appears safe, additional participants in a second cohort will receive an increased dose of PMR-116 to be taken at set times throughout a 28-day treatment cycle. Up to 5 increasing doses will be investigated in separate treatment cohorts until the maximum safe dose has been determined. Following Dose Escalation will be Dose Schedule Optimization. Dose Schedule Optimisation will also assess the safety and tolerability of PMR-116 and identify the maximum feasible dose and the dose administration schedule. All participants will undergo the same assessments as listed in the Dose Escalation portion of the study, however 3 dosing schedules of 2-days dosing/5-days off; 3-days dosing/4-days off & 4-days dosing/10-days off will be explored. Dose levels explored will not exceed 1800mg/week.
Participants enrolled in the Dose Expansion and Dose Schedule Optimization phases of the study will be asked to provide a sample of their archival tumour before commencing PMR-116 treatment.,

In the second study part (Dose expansion), a new cohort of participants will receive multiple doses of the maximum safe dose of PMR-116 to be taken at set times throughout a 28-day treatment cycle. All participants will have their vital signs checked and will provide blood and urine samples for testing. Participants enrolled in the dose expansion study will also be asked to provide a sample of their tumour (taken by a biopsy) before starting and again 22 days after starting PMR-116 treatment,

It is hoped this research will determine the maximum dose of PMR-116 that can be administered safely without causing severe reactions. Once the dose of PMR-116 has been determined, a larger trial investigating the efficacy of PMR-116 as a treatment for cancer patients with advanced solid tumours may pr
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 104974 0
A/Prof Jayesh Desai
Address 104974 0
Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne, Victoria 3000
Country 104974 0
Australia
Phone 104974 0
+61 3 8559 5000
Fax 104974 0
+61 3 8559 7379
Email 104974 0
[email protected]
Contact person for public queries
Name 104975 0
Ms Cara Casseday
Address 104975 0
Pimera, Inc.
3210 Merryfield Row
San Diego, California, 92128
Country 104975 0
United States of America
Phone 104975 0
+1 858 204 9319
Fax 104975 0
Email 104975 0
[email protected]
Contact person for scientific queries
Name 104976 0
Ms Cara Casseday
Address 104976 0
Pimera, Inc.
3210 Merryfield Row
San Diego, California, 92128
Country 104976 0
United States of America
Phone 104976 0
+1 858 204 9319
Fax 104976 0
Email 104976 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
Commercial information


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.