Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000856718
Ethics application status
Approved
Date submitted
21/05/2022
Date registered
17/06/2022
Date last updated
17/06/2022
Date data sharing statement initially provided
17/06/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
A First-in-Human Study of Single-Agent ISB 1442 in Patients with Relapsed/Refractory Multiple Myeloma
Scientific title
A Phase 1/2, First-in-Human, Multicenter, Open-Label, Dose Escalation and Dose-Expansion Study assessing safety and tolerability of Single-Agent ISB 1442 in Patients with Relapsed/Refractory Multiple Myeloma
Secondary ID [1] 307015 0
ISB 1442-101
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Relapsed Multiple Myeloma 326140 0
Refractory Multiple Myeloma 326141 0
Condition category
Condition code
Cancer 323458 323458 0 0
Myeloma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
ISB 1442 is a potential first-in-class CD38 x CD47 bispecific, biparatopic antibody generated using Ichnos’ BEAT® 2.0 technology. ISB 1442 is designed to kill CD38-expressing tumor cells
The Study consists of two parts
Phase 1 (Dose Escalation phase)
Investigational Product (IP): ISB 1442
Dosage Form: Lyophilized powder
Mode of Administration: Subcutaneous (SC) Injection
Dosage frequency: For all cohorts, dosing will occur once on Days 1, 8, 15, and 22 of each 28-day cycle, for a maximum of typically approximately 4 cycles. However, the maximum number of cycles could be endless, as participants may continue on the assigned dose within their cohort until disease progression, intolerability or withdrawal of consent.
Cohort 1: 6 mg of ISB 1442 administered once on Days 1, 8, 15 and 22 of each 28-day cycle
Cohort 2: 20 mg of ISB 1442 administered once on Days 1, 8, 15 and 22 of each 28-day cycle
Cohort 3: 60 mg of ISB 1442 administered once on Days 1, 8, 15 and 22 of each28-day cycle
Cohort 4: 150 mg of ISB 1442 administered once on Days 1, 8, 15 and 22 of each 28-day cycle
Cohort 5: 300 mg of ISB 1442 administered once on Days 1, 8, 15 and 22 of each 28-day cycle
Cohort 6: 600 mg of ISB 1442 administered once on Days 1, 8, 15 and 22 of each 28-day cycle
Cohort 7: 1200 mg of ISB 1442 administered once on Days 1, 8, 15, 22 of each 28-day cycle
Dose escalation will continue until either Maximum Tolerated Dose (MTD) is defined, the maximum planned dose is reached, or a recommended Phase 2 dose (RP2D) is selected.
Decisions with regards to step-up/priming dose levels and schedule will be made by the Safety Monitoring Committee (SMC)
To allow for assessment of safety, the dosing of all patients within each dose level cohort should be staggered with at least 24 hours between each patient. Agreement from the SMC must be obtained before treatment of the next dose escalation cohort can start.
The IP will be administered subcutaneously by authorized site staff once weekly on Days 1, 8, 15, 22 in a 28-day cycle for all cohorts.
Phase 2 (Dose Expansion Phase)
Investigational Product: ISB 1442
Dosage Form: Lyophilized powder
Mode of Administration: Subcutaneous (SC) Injection
About 4-8 weeks after the recommended Phase 2 dose (RP2D) of ISB 1442 is established in Phase 1, Phase 2 expansions will be initiated to further evaluate safety and efficacy of ISB 1422.
The phase 2 of study will enroll two distinct cohorts (Cohort A: Relapsed/Refractory (R/R) Multiple Myeloma (MM) and Cohort B: R/R MM Post-T-Cell-Directed Therapy) of participants.
The participants in each cohort will receive ISB 1442 on day 1, 8, 15 and 22 of each 28-day cycles, for a maximum of typically approximately 12 cycles, however, the maximum number of cycles could be endless, as participants may continue on the assigned Phase 2 dose until disease progression, intolerability or withdrawal of consent.
The IP will be administered subcutaneously by authorized site staff once weekly on Days 1, 8, 15, 22 in a 28-day cycle.
The phase 1 and phase 2 of the study will enroll distinct group of participants.
Intervention code [1] 323472 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 331211 0
Phase 1: Assess safety and tolerability of ISB 1442 through frequency and severity of treatment-emergent adverse events (TEAEs) graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Timepoint [1] 331211 0
Phase 1: Up to 60 months from initiation of the study, or to last patient dosed, whichever comes first.
Primary outcome [2] 331212 0
Phase 1: Determine maximum tolerated dose (MTD) and/or RP2D through the incidence of dose limiting toxicities (DLT)
Examples of DLTs that may be experienced by participants include, but are not limited to, allergic reactions, infusion related reactions, injection site reactions, tumor lysis syndrome, nausea/vomiting or diarrhea, fatigue and hemolytic anemia.
Timepoint [2] 331212 0
Phase 1: During the first 28 days after the first administration of study drug (ie, Cycle 1) in each cohort
Primary outcome [3] 331213 0
Phase 2: Evaluate efficacy of ISB 1442
Multiple myeloma: Overall response rate (ORR) (response of at least partial response [PR] or better) based on Investigator’s assessment according to International Myeloma Working Group (IMWG) disease response criteria
Timepoint [3] 331213 0
Phase 2: ORR will be assessed every 4 weeks (7 days) for the first 12 months then every 8 weeks (7 days) thereafter, until disease progression, intolerability or withdrawal of consent.
Secondary outcome [1] 409206 0
Phase 1/Phase 2: Characterize the pharmacokinetic (PK) profile of ISB 1442
Serum sample will be obtained for PK analysis

Parameters:
•Cmax
•Time to reach maximum plasma concentration following drug administration (tmax)
• Area under the serum concentration-time curve over a dosing interval (AUC0-tau)
•Area under the serum concentration-time curve over the time interval from zero to last
quantifiable concentration (AUC0-t)
•Area under the serum concentration-time curve over the time interval from zero extrapolated
to infinity (AUC0-infinity)
•Terminal half-life (t½)
•Mean residence time after IV infusion (MRT)
•Total serum clearance (CL)
•Apparent volume of distribution during the terminal phase (Vz)
•Volume of distribution after IV infusion at steady state (Vss)
Timepoint [1] 409206 0
For Cycle 1
• Day 1: pre-dose and 2h(±15min), 4h(±20min) and 8h(±30min) post dose administered on Day 1
• Day 2: 24h(±120min) and 36h(±240min) post dose administered on Day 1
• Day 3: for participants with additional step up doses only = pre-dose and 2h(±15min), 4h(±20min) and 8h(±30min) post dose administered on Day 3
• Day 4: 72h(+48hmin) post dose administered on Day 1
• Day 8: pre-dose and 2h(±15min), 4h(±20min) and 8h(±30min) post dose administered on Day 8
• Day 9: 24h(±120min) and 36h(±240min) post dose administered on Day 8
• Day 10: for participants with additional step up doses only = pre-dose and 2h(±15min), 4h(±20min) and 8h(±30min) post dose administered on Day 10
• Day 11: 72h (±48min) post dose administered on Day 8
• Day 15: pre-dose
• Day 22: pre-dose

For Subsequent cycles
• Day 1: pre-dose
• Day 8: pre-dose
• Day 15: pre-dose
• Day 22: pre-dose
• End of Treatment visit: Defined as discontinuation (permanent stopping) of study treatment with investigational product for any reason, upon assessment and decision by the Investigator. This could occur at any time during the participation of the study.
• 1 month Safety Follow Up visit
Secondary outcome [2] 409207 0
Phase 1/Phase 2: Characterize immunogenicity of ISB 1442 through percent incidence of anti-drug antibody (ADA), neutralizing antibody (nAb) and titer of ADA. This is composite secondary outcome.
Whole blood sample will be collected for immunogenicity assessment
Timepoint [2] 409207 0
Cycle 1: Day 1, Day 8 and Day 15 post dose administration
For subsequent cycles: Up to 60 months from initiation of the study, or to last patient dosed, whichever comes first.
Secondary outcome [3] 410134 0
Phase 1: Assess preliminary efficacy of ISB 1442
1. Analysis of time to event endpoints: time to progression (TTP), time to next treatment (TTNT), time to response (TTR), progression free survival (PFS), overall survival (OS), duration of response (DOR) will be performed according to the Kaplan-Meier method and the 95% CIs of the median will be provided.

Time to Progression (TTP) is defined as the time from the date of the first dose to the date of the first documentation of progressive disease as defined by standard disease criteria.
Progression will be assessed by measurement of circulating M-protein (peripheral blood draw), a bone marrow biopsy/aspirate is not required but may be performed as part of standard of care
Time to New Treatment (TTNT) is defined as the time from the date of first dose randomisation to the date of the first dose initiation of the next line of antineoplastic therapy, for any reason. Patients who have not started the second-line therapy will be censored at date of last known to be alive subsequent anti-cancer therapy. New treatment start date will be captured from patient medical records and/or follow-up calls as part of Survival Follow-Up
Time to To Response (TTR) is the time from the date of the first dose to the date of the first documentation of objective response [response of Partial Response or better for MM] as defined by standard disease criteria. Response to treatment will be assessed by measurement of circulating M-protein (peripheral blood draw) and for patients with extramedullary disease at enrollment, the same imaging as performed for screening; a bone marrow biopsy/aspirate biopsy to confirm response for patients with a response of very good partial response (VGPR) or better.
Progression Free Survival (PFS) is defined as the time from the date of the first dose administration to the date of first documentation of progressive disease or death due to any cause, whichever occurs first. Progressive disease will be determined by standard disease criteria. Patients without documentation of progressive disease will be censored at the date of the last response assessment. Progression will be assessed by measurement of circulating M-protein (peripheral blood draw), a biopsy is not required but may be performed as part of standard of care.
Overall Survival (OS) is defined as the time from the date of randomisation to the date of death. Patients without documentation of death at the time of analysis will be censored at the date last known to be alive. Survival will be captured from patient medical records and/or follow-up calls as part of Survival Follow-Up
Duration of Response (DOR) is the time from the date of first documentation of a Partial Response (PR) or better to the date of first documentation of progressive disease for responders (PR or better). Responders without documentation of progressive disease will be censored at the date of last response assessment that is stable disease or better. Patients who present with response to treatment will continue to be assessed by circulating M-protein (peripheral blood draw), patients with a complete response (CR) or better and are minimal residual disease (MRD) negative will be assessed for MRD status every six months (bone marrow aspirate)

2. Investigator-assessed overall response rate (ORR) and complete response rate (CRR) based on International Myeloma Working Group (IMWG) for Multiple Myeloma with 95% confidence intervals (Cis) will be presented.
This is a composite secondary outcome.
Timepoint [3] 410134 0
Phase 1: Up to 60 months from initiation of the study, or to last patient dosed, whichever comes first.
Secondary outcome [4] 410137 0
Phase 2: Assess safety and tolerability of ISB 1442 through frequency and severity of treatment-emergent adverse events (TEAEs) graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Timepoint [4] 410137 0
Phase 2: Up to 60 months from initiation of the study, or to last patient dosed, whichever comes first.
Secondary outcome [5] 410138 0
Phase 2: Further characterize efficacy of ISB 1442
1. Analysis of time to event endpoints: time to progression (TTP), time to next treatment (TTNT), time to response (TTR), progression free survival (PFS), overall survival (OS), duration of response (DOR) will be performed according to the Kaplan-Meier method and the 95% confidence intervals (CIs) of the median will be provided.

Time to Progression (TTP) is defined as the time from the date of the first dose to the date of the first documentation of progressive disease as defined by standard disease criteria.
Progression will be assessed by measurement of circulating M-protein (peripheral blood draw), a bone marrow biopsy/aspirate is not required but may be performed as part of standard of care
Time to New Treatment (TTNT) is defined as the time from the date of first dose randomisation to the date of the first dose initiation of the next line of antineoplastic therapy, for any reason. Patients who have not started the second-line therapy will be censored at date of last known to be alive subsequent anti-cancer therapy. New treatment start date will be captured from patient medical records and/or follow-up calls as part of Survival Follow-Up
Time to To Response (TTR) is the time from the date of the first dose to the date of the first documentation of objective response [response of Partial Response or better for MM] as defined by standard disease criteria. Response to treatment will be assessed by measurement of circulating M-protein (peripheral blood draw) and for patients with extramedullary disease at enrollment, the same imaging as performed for screening; a bone marrow biopsy/aspirate biopsy to confirm response for patients with a response of very good partial response (VGPR) or better.
Progression Free Survival (PFS) is defined as the time from the date of the first dose administration to the date of first documentation of progressive disease or death due to any cause, whichever occurs first. Progressive disease will be determined by standard disease criteria. Patients without documentation of progressive disease will be censored at the date of the last response assessment. Progression will be assessed by measurement of circulating M-protein (peripheral blood draw), a biopsy is not required but may be performed as part of standard of care.
Overall Survival (OS) is defined as the time from the date of randomisation to the date of death. Patients without documentation of death at the time of analysis will be censored at the date last known to be alive. Survival will be captured from patient medical records and/or follow-up calls as part of Survival Follow-Up
Duration of Response (DOR) is the time from the date of first documentation of a Partial Response (PR) or better to the date of first documentation of progressive disease for responders (PR or better). Responders without documentation of progressive disease will be censored at the date of last response assessment that is stable disease or better. Patients who present with response to treatment will continue to be assessed by circulating M-protein (peripheral blood draw), patients with a complete response (CR) or better and are minimal residual disease (MRD) negative will be assessed for MRD status every six months (bone marrow aspirate)

2. Investigator-assessed overall response rate (ORR) based on International Myeloma Working Group (IMWG) for Multiple Myeloma with 95% CIs will be presented.

This is a composite secondary outcome.
Timepoint [5] 410138 0
Phase 2: Up to 60 months from initiation of the study, or to last patient dosed, whichever comes first.

Eligibility
Key inclusion criteria
1. Male or female patients aged 18 years or older.
2. Willing and able to provide written informed consent.
3. Patients with pathologically confirmed and measurable multiple myeloma (MM) who have progressed on or after standard therapy.
4. Patients must have received: a proteosome inhibitor (PI), a immune modulator (IMiD), and an anti-CD38 therapies either in combination or as a single agent; and must not be candidates for regimens known to provide clinical benefit.
5. Body weight more than 40.0 kg.
6. Patients must have adequate hematologic and organ function laboratory values.
7. Left ventricular ejection fraction (LVEF) more than 45% as assessed by echocardiogram (ECHO) or multiple gated acquisition (MUGA) scan.
8. Have a negative serum pregnancy test result at screening for women of childbearing potential.
9. Must agree to acceptable contraception.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Cannot have diagnosis of primary amyloidosis, Waldenström’s disease, smoldering multiple myeloma, POEMS syndrome, myelodysplastic syndrome, or myeloproliferative syndrome.
2. Cannot have prior treatment or radiation within 14 days before first dose of study drug.
3. Cannot have autologous stem cell transplantation within 12 weeks of first dose of study drug.
4. Cannot have other investigation agent, live vaccine, or major surgery within 4 weeks of first dose of study drug.
5. Cannot have known history of human immunodeficiency virus (HIV) infection or any other relevant congenital or acquired immunodeficiency.
6. Cannot have history of allogeneic tissue or solid organ transplant.
7. Cannot have history of any of congestive heart failure, unstable angina, myocardial infarction, unstable symptomatic ischemic heart disease, uncontrolled hypertension despite appropriate medical therapy, symptomatic cardiac arrhythmias, pulmonary embolism or any other serious cardiac condition within 6 months of first dose of study drug.

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
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
25/07/2022
Actual
Date of last participant enrolment
Anticipated
14/11/2025
Actual
Date of last data collection
Anticipated
1/05/2027
Actual
Sample size
Target
121
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,TAS,WA,VIC
Recruitment hospital [1] 22307 0
Gold Coast University Hospital - Southport
Recruitment hospital [2] 22358 0
One Clinical Research - Nedlands
Recruitment hospital [3] 22404 0
Hollywood Private Hospital - Nedlands
Recruitment hospital [4] 22405 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [5] 22406 0
Pindara Private Hospital - Benowa
Recruitment hospital [6] 22407 0
The Alfred - Melbourne
Recruitment hospital [7] 22408 0
Royal Hobart Hospital - Hobart
Recruitment hospital [8] 22462 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment postcode(s) [1] 37469 0
4215 - Southport
Recruitment postcode(s) [2] 37520 0
6009 - Nedlands
Recruitment postcode(s) [3] 37569 0
2050 - Camperdown
Recruitment postcode(s) [4] 37570 0
4217 - Benowa
Recruitment postcode(s) [5] 37571 0
3004 - Melbourne
Recruitment postcode(s) [6] 37572 0
7000 - Hobart
Recruitment postcode(s) [7] 37696 0
3065 - Fitzroy

Funding & Sponsors
Funding source category [1] 311325 0
Commercial sector/Industry
Name [1] 311325 0
Ichnos Sciences SA
Country [1] 311325 0
Switzerland
Primary sponsor type
Commercial sector/Industry
Name
Ichnos Sciences SA
Address
Chemin de la Combeta 5
La Chaux-de-Fonds, NE 2300 CH
Country
Switzerland
Secondary sponsor category [1] 312816 0
None
Name [1] 312816 0
Address [1] 312816 0
Country [1] 312816 0
Other collaborator category [1] 282294 0
Commercial sector/Industry
Name [1] 282294 0
Novotech (Australia) Pty Limited
Address [1] 282294 0
Level 3, 235 Pyrmont street, Pyrmont NSW 2009
Country [1] 282294 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310826 0
Bellberry Human Research Ethics Committee C
Ethics committee address [1] 310826 0
Ethics committee country [1] 310826 0
Australia
Date submitted for ethics approval [1] 310826 0
13/04/2022
Approval date [1] 310826 0
17/05/2022
Ethics approval number [1] 310826 0
2022-04-343
Ethics committee name [2] 310849 0
Human Research Ethics Committee, Gold Coast Hospital and Health Service
Ethics committee address [2] 310849 0
Ethics committee country [2] 310849 0
Australia
Date submitted for ethics approval [2] 310849 0
12/05/2022
Approval date [2] 310849 0
Ethics approval number [2] 310849 0

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

Contacts
Principal investigator
Name 119002 0
A/Prof Peter Tan
Address 119002 0
One Clinical Research,
Suite 3A, 85 Monash Avenue, Nedlands, WA 6009
Country 119002 0
Australia
Phone 119002 0
+618 6424 8105
Fax 119002 0
Email 119002 0
peter.tan@oneclinicalresearch.com.au
Contact person for public queries
Name 119003 0
Amy Conrad-Smith
Address 119003 0
Novotech (Australia) Pty Limited
Level 3, 235 Pyrmont street, Pyrmont NSW 2009
Country 119003 0
Australia
Phone 119003 0
+61 2 8569 1400
Fax 119003 0
Email 119003 0
Amy.Conrad-Smith@novotech-cro.com
Contact person for scientific queries
Name 119004 0
Amy Conrad-Smith
Address 119004 0
Novotech (Australia) Pty Limited
Level 3, 235 Pyrmont street, Pyrmont NSW 2009
Country 119004 0
Australia
Phone 119004 0
+61 2 8569 1400
Fax 119004 0
Email 119004 0
Amy.Conrad-Smith@novotech-cro.com

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.