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Trial registered on ANZCTR

Registration number

ACTRN12624001123538

Ethics application status

Approved

Date submitted

30/07/2024

Date registered

18/09/2024

Date last updated

18/09/2024

Date data sharing statement initially provided

18/09/2024

Type of registration

Prospectively registered

Titles & IDs

Public title

Phase 1 Trial of ITM-22 in Patients with Prostate-Specific Membrane Antigen (PSMA)-positive Progressive Metastatic Castration Resistant Prostate Cancer

Scientific title

A Multicentre, Open-label, Interventional, Repeated Dose Escalation/De-escalation Phase I Trial to Determine the Optimal Biological Dose, and Evaluate Safety, Pharmacokinetics and Preliminary Efficacy of Actinium (225Ac) Ibu-DAB-PSMA for the Treatment of PSMA-positive Progressive Metastatic Castration Resistant Prostate Cancer

Secondary ID [1]

ITM-2221-01CT

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Progressive metastatic castration resistant prostate cancer (mCRPC)

Condition category

Condition code

Cancer

Prostate

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Treatment with radiotherapeutic Actinium (225Ac) Ibu-DAB-PSMA (ITM-22) will be carried out in 2 phases.

Phase I part of the trial is to determine the actinium (225Ac) Ibu-DAB-PSMA optimal biological dose based on the number of evaluable participants reaching a PSA response (a PSA decrease of =30%) and the number of evaluable participants experiencing safety limiting events within 8 weeks from the first dose.

The treatment with actinium (225Ac) Ibu-DAB-PSMA will consist of a maximum of 12 MBq of cumulative injected activity administered as a slow bolus injection at different dose levels and a varying number of treatment cycles. The Nuclear Medicine Physician will administer the intervention in consultation with the Medical Oncologist.

Each cycle, regardless of the dose activity, will be administered at 8-week intervals (authorised window: not less than 6 weeks and up to 13 weeks to allow toxicity recovery and investigational medicinal product (IMP) ordering) or until diagnosis of disease progression as determined by the Investigator, death, intolerable toxicity, trial treatment consent withdrawal or lost to follow-up, whichever occurs earlier. Each set of evaluable participants will consist of 3 participants who received the same DL at a time.

The trial will follow an adaptive Bayesian Optimal Interval design. Actinium (225Ac) Ibu-DAB-PSMA dose escalation and de-escalation procedure will include:
• Dose Level 1 (DL1): receiving 2 ± 0.2 MBq, for Cycles 1 to 6, total duration 48 weeks
• Dose Level 2 (DL2): receiving 4 ± 0.4 MBq, for Cycles 1 to 3, total duration 24 weeks
• Dose Level 3 (DL3): receiving 6 ± 0.6 MBq, for Cycles 1 to 2, total duration 16 weeks

In the Phase I part of the trial using BOIN12 designs, safety limiting events (SLEs) and prostate-specific antigen (PSA) response will be analysed to inform the DMC on the toxicity and efficacy profile presented in each Dose Level (DL). The proportion of participants at each DL with toxicity and efficacy outcomes will be used to determine the desirability of each DL.

A Data Monitoring Committee (DMC) will be responsible for monitoring the safety of study participants. Frequency of DMC meetings will depend on recruitment speed. DMC meetings will take place after each cohort (3 pts) is dosed in Phase I (after Cycle 1). The DMC will review safety, efficacy and dosimetry data, the relevant information on safety profiles of the IMP, SLEs and PSA response and the toxicity and efficacy profile presented in each DL.

Once a dose level maximum has been continually established (12 participants per dose level), or the maximum sample size has been reached (24 participants overall); the two doses with the highest desirability scores will be carried across into a Phase II of the trial.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

There is no comparator group for this study.

Control group

Uncontrolled

Outcomes

Primary outcome [1]

Phase 1 - Determine the actinium (225Ac) Ibu-DAB-PSMA optimal biological dose.

Timepoint [1]

Number of evaluable participants reaching prostate-specific antigen (PSA) decline of =30% within 8 weeks from the first dose.
-PSA efficacy assessments are every 4 ± 1 week from the first IMP administration during treatment period and then after end of last treatment (EOLT) every 12 ± 2 weeks until documented PSA progression (PSA increased greater than or equal to 25% and greater than or equal to 2 ng/mL over nadir on 2 consecutive assessments measured at least 3 weeks apart) or EOT, whichever occurs earlier (can be coupled with other visits when possible), unless the participant started a new anti-cancer treatment.

Number of evaluable participants experiencing safety limiting events (predefined events considered related to the investigational drug, including non-haematologic and haematologic toxicities, and also any death not related to either the underlying disease or extraneous causes) within 8 weeks from the first dose.
-SLEs safety labs assessments (haematology and biochemistry parameters) are to be performed every 2 ± 1 weeks from first treatment until EOLT.

Secondary outcome [1]

Phase 1 - To further characterise and confirm the safety and tolerability of actinium (225Ac) Ibu-DAB-PSMA.

Timepoint [1]

Information about AEs and SAEs will be collected from signing the Informed Consent Form (ICF) until 50 days (5 half-lives) following the last dose of trial treatment or until end of last treatment visit, whichever occurs later.

The occurrence of AEs will be questioned/collected from the participant at each visit during the trial. AEs also may be detected when they are volunteered by the participant during or between visits or through physical examination findings, laboratory test findings, or other assessments, including relevant patient-oriented outcome questionnaires (e.g., xerostomia or pain questionnaires).

Safety labs and vital signs will be collected at screening, during treatment period until end of trial.

Xerostomia questionnaire will be performed every 4 ± 1 weeks during treatment until end of last treatment and then after end of last treatment every 12 ± 2 weeks during the long-term follow-up, until end of trial.

Secondary outcome [2]

Phase 1 - Evaluate preliminary efficacy signals of actinium (225Ac) Ibu-DAB-PSMA in the treatment of progressive mCRPC by analysis of rPFS and rPFS rates.

Timepoint [2]

rPFS and rPFS rates are analysed at 3, 5, 7, 10 and 13 months starting after first IMP administration.

Secondary outcome [3]

Phase 1 - Evaluate preliminary efficacy signals of actinium (225Ac) Ibu-DAB-PSMA in the treatment of progressive mCRPC by analysis of objective response rates (ORR).

Timepoint [3]

At 3, 5, 7, 10 and 13 months starting after first IMP administration.

Secondary outcome [4]

Phase 1 - Evaluate preliminary efficacy signals of actinium (225Ac) Ibu-DAB-PSMA in the treatment of progressive mCRPC by analysis of PSA decrease.

Timepoint [4]

At 3, 5, 7, 10 and 13 months starting after first IMP administration.

Secondary outcome [5]

Phase 1 - Evaluate preliminary efficacy signals of actinium (225Ac) Ibu-DAB-PSMA in the treatment of progressive mCRPC by analysis of duration of responses.

Timepoint [5]

PSMA PET/CT first tumour assessment (12 ± 2 weeks) and at every 8 ± 1 weeks until week 28. After week 28, the assessments will be every 12 ± 2 weeks until documented RECIP 1.0 disease progression or EOT, whichever occurs earlier, unless the participant started a new anti-cancer treatment.

PSA assessments will be performed every 4 ± 1 weeks from first IMP administration during treatment until EOLT and then after EOLT every 12 ± 2 weeks during the long-term follow-up.

Secondary outcome [6]

Phase 1 - Evaluate preliminary efficacy signals of actinium (225Ac) Ibu-DAB-PSMA in the treatment of progressive mCRPC by analysis of time to progressions by morphological imaging.

Timepoint [6]

Morphological imaging first tumour assessment at 12 ± 2 weeks and at every 8 ± 1 weeks until week 28. After week 28, the assessments will be every 12 ± 2 weeks. Follow-up assessments should be continued until first radiographical disease progression is documented according to PCWG3 criteria or until EOT, whichever occurs earlier, unless the participant started a new anti-cancer treatment.

Secondary outcome [7]

Phase 1 - Evaluate preliminary efficacy signals of actinium (225Ac) Ibu-DAB-PSMA in the treatment of progressive mCRPC by analysis of Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire.

Timepoint [7]

Completed by participants every 4 ± 1 weeks during the treatment period until EOLT visit and then every 12 ± 2 weeks during the follow-up (until EOT visit).

Secondary outcome [8]

Phase 1 - Evaluate preliminary efficacy signals of actinium (225Ac) Ibu-DAB-PSMA in the treatment of progressive mCRPC by analysis of analgesics consumption.

Timepoint [8]

Up to 30 days prior to enrolment and continuously until EOT.

Secondary outcome [9]

Phase 1 - Evaluate preliminary efficacy signals of actinium (225Ac) Ibu-DAB-PSMA in the treatment of progressive mCRPC by analysis of time to first symptomatic skeletal event (SSE).

Timepoint [9]

From signing the ICF and continuously until EOT.

Secondary outcome [10]

Phase 1 - Evaluate preliminary efficacy signals of actinium (225Ac) Ibu-DAB-PSMA in the treatment of progressive mCRPC by analysis of time to progressions in PSA levels.

Timepoint [10]

PSA assessments will be performed every 4 ± 1 weeks from first IMP administration during treatment until EOLT and then after EOLT every 12 ± 2 weeks during the long-term follow-up.

Secondary outcome [11]

Phase 1 - Evaluate preliminary efficacy signals of actinium (225Ac) Ibu-DAB-PSMA in the treatment of progressive mCRPC by analysis of time to progressions by PSMA PET/CT imaging.

Timepoint [11]

PSMA PET/CT imaging first tumour assessment at 12 ± 2 weeks and at every 8 ± 1 weeks until week 28. After week 28, the assessments will be every 12 ± 2 weeks until documented RECIP 1.0 disease progression or EOT, whichever occurs earlier, unless the participant started a new anti-cancer treatment.

Secondary outcome [12]

Phase 1 - Evaluate preliminary efficacy signals of actinium (225Ac) Ibu-DAB-PSMA in the treatment of progressive mCRPC by analysis of Brief Pain Inventory – Short Form (BPI-SF) questionnaire.

Timepoint [12]

Completed by participants every 4 ± 1 weeks during the treatment period until EOLT visit and then every 12 ± 2 weeks during the follow-up (until EOT visit).

Secondary outcome [13]

Phase 1 Exploratory - Assess pharmacokinetics (PK) and dosimetry of actinium (225Ac) Ibu-DAB-PSMA.

Timepoint [13]

Participants will undergo dosimetry and PK assessments using imaging as well as blood and urine sampling as follows:
-Blood samples will be collected at 0 to 5 minutes, 10 to 15 minutes, 25 to 35 minutes, 60 ± 10 minutes, and then at 3 ± 1 hours, 6 ± 1 hours, 24 ± 3 hours, 48 ± 3 hours, 96 ± 24 hours and 168 ± 24 hours after IMP administration (168 ± 24 hours post injection measurements might be omitted for later participants of a DL if no relevant signals are found for Cycle 1 of the first 3 participants in each DL).
-Urine samples will be collected at 60 ± 10 minutes, 6 ± 1 hours, 24 ± 3 hours, 48 ± 3 hours and 96 ± 24 hours after IMP administration.
-Whole body planar gamma camera assessments will be performed at 25 to 35 minutes, 3 ± 1 hours, 6 ± 1 hours, 24 ± 3 hours, 48 ± 3 hours, 96 ± 24 for later participants of a DL if no relevant signals are found for Cycle 1 of the first 3 participants in each DL).
-Abdominal SPECT/CT assessments will be performed at 6 ± 1 hours, 24 ± 3 hours, and 48 ± 3 hours after IMP administration.

Secondary outcome [14]

Phase 1 Exploratory - Comparison of presence of visceral (lung, liver, adrenals and central nervous system) metastases and its association with participants’ biochemical response, rPFS and overall survival (OS).

Timepoint [14]

The presence of visceral metastases during screening will be recorded.

Eligibility

Key inclusion criteria

1. Male participants greater than or equal to 18 years of age
2. Provided written informed consent to participate in the trial
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2
4. Histologically, pathologically, and/or cytologically confirmed metastatic adenocarcinoma of the prostate without significant (i.e., > 10%) sarcomatoid or spindle or neuroendocrine or small cell differentiation components
5. Stage IV prostate cancer with at least one lesion that is measurable on baseline CT or MRI, or present on bone scan imaging, obtained within 30 days prior to trial enrolment as per PCWG3 criteria
6. At least one PSMA PET/CT positive lesion (i.e., higher than liver uptake) within 30 days prior to enrolment
7. Serum/plasma PSA level > 2 ng/mL within 30 days prior to enrolment and progressing (greater than or equal to 25% and greater than or equal to 2 ng/mL) over a previous reference value measured at least 1 week prior
8. Castrate level of serum/plasma testosterone (i.e., less than or equal to 50 ng/dL or less than or equal to 1.73 nmol/L) obtained either by bilateral orchiectomy or by ongoing treatment with a fixed dose of a luteinizing hormone-releasing hormone (LHRH) analogue (agonist or antagonist). Participants without prior surgical castration must have initiated a LHRH analogue treatment at least 14 days before enrolment, which should be maintained at the same dose during the trial until documented radiographic progression according to PCWG3 criteria

Minimum age

18 Years

Maximum age

No limit

Sex

Males

Can healthy volunteers participate?

Key exclusion criteria

All participants will be excluded from participation in the trial if one or more of the following criteria are met:
1. Having received more than 2 previous doses of PSMA-targeted radiopharmaceutical therapy (RPT). Last targeted RPT dose should have been administered greater than or equal to 12 weeks prior to enrolment to be eligible
2. Last treatment with external beam radiotherapy, or with radioactive bone-seekers should have been administered greater than or equal to 12 weeks prior to enrolment
3. Having received more than 3 systemic lines of therapy overall (luteinizing hormone-releasing hormone (LHRH) analogues excluded), regardless of the castration sensitivity status
4. One or more of the following PSMA PET/CT negative lesion types:
a. greater than or equal to 1.0 cm soft tissue component in a bone metastatic lesion
b. greater than or equal to 2.5 cm lymph node metastatic lesion
c. greater than or equal to 1.0 cm solid organ metastatic lesion
5. Any systemic anti-cancer therapy within 30 days prior to trial enrolment (except Androgen receptor axis targeted therapy (ARAT) for which 7 days are sufficient and except LHRH analogues without time restriction)
6. Any investigational therapeutic agents within 30 days or 5 half-life periods, whichever is longer, prior to trial enrolment
7. Major surgery within 30 days prior to trial enrolment
8. Received a live attenuated vaccine within 30 days prior to trial enrolment
9. Known hypersensitivity to the components of the trial therapy or its analogues.
10. History of brain metastases or leptomeningeal metastases. A scan to confirm the absence of brain metastases is not required if there is no history of this
11. Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression unless appropriately treated beforehand and clinically stable for greater than or equal to 30 days
12. Severe uncontrolled non-malignant disease (e.g., psychiatric, infectious, autoimmune, metabolic or dementia), that may interfere with the objectives of the trial or with the safety or compliance of the participant, as judged by the Investigator. Specific attention should be paid to the risk of bleeding that is not properly treated and controlled, such as epistaxis, oesophageal varices or gastrointestinal bleeding
13. Diagnosed with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. However, participants with such a prior history of other malignancy that has been adequately treated and who have been disease free for at least 3 years are eligible, as are, with no time restriction, participants with adequately treated low-grade malignancies which have low risk of recurrence such as non-melanoma skin cancer or superficial bladder cancer
14. Renal, hepatic, cardiovascular, or haematological organ dysfunction, potentially interfering with the safety of the trial treatments, including the following:
a. Renal:
i. Estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73 m2 (calculated by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] 2021 formula [local laboratory])
ii. Urinary tract obstruction or hydronephrosis unless effective catheterisation is in place
b. Hepatic:
i. Total bilirubin > 2 × upper limit of normal (ULN) or > 3 × ULN for participants with Gilbert’s disease or liver metastases
ii. Albumin < 30 g/L
iii. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 × ULN, with the exception that participants with liver metastasis must have AST and/or ALT less than or equal to 5 × ULN
c. Haematologic:
i. Platelet count less than or equal to 100 × 109/L
ii. Absolute neutrophil count (ANC) < 1.5 × 109 cells/L
iii. Haemoglobin concentration < 6.2 mmol/L (< 10.0 g/dL; measured at least 30 days after a previous transfusion if any given to the participant)
d. Cardiovascular:
i. Congestive heart failure (New York Heart Association [NYHA] classification III and IV), unstable angina
ii. A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval > 450 milliseconds
iii. History or current diagnosis of ECG abnormalities indicating significant risk of safety for trial participants
15. Any ongoing greater than or equal to Grade 2 toxicities related to prior therapies, with the exception of alopecia of any grade, stable treated electrolyte abnormalities on replacement and Grade 2 peripheral neuropathy from previous standard or investigational therapies (Common Terminology Criteria for Adverse Events [CTCAE] version 5.0)
16. Male participants with female partners of childbearing potential, unless:
a. willing to practice full and true sexual abstinence, or
b. are surgically/permanently sterile (bilateral tubal occlusion, hysterectomy, or vasectomy), or
c. are willing to practice highly effective contraception in combination with a barrier method of contraception (e.g., condom). Contraception methods that are considered highly effective are: oral or non-oral (injected or implanted) non-oestrogen progesterone-based hormonal method; oral, intravaginal, or transdermal combined oestrogen and progesterone-based hormonal methods; and/or intrauterine device, and/or intrauterine hormone-releasing system. Sexual abstinence or the contraception methods described above must be followed throughout the entire trial period and for at least 14 weeks (half-lives of actinium-225 is 9.92 days) after the last treatment cycle
17. Current unmanageable urinary incontinence preventing safe administration of the IMP, in the Investigator’s opinion
18. Not able to declare meaningful informed consent on his own (e.g., with legal guardian for mental disorders) or any other vulnerable population to that sense (e.g., persons institutionalised, incarcerated etc.)

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

Safety/efficacy

Statistical methods / analysis

The Phase I part of the trial will be performed using a BOIN12 design. The coprimary focus will be on efficacy and toxicity. This Phase I will not be formally comparative, with statistical analysis focusing on the proportion of participants at each DL, with each level being considered individually. As more participants get added to the dose, the information will be updated in a Bayesian framework.

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

30/09/2024

Actual

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW,QLD

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

ITM Oncologics GmbH

Address [1]

Country [1]

Germany

Primary sponsor type

Commercial sector/Industry

Name

ITM Oncologics GmbH

Address

Country

Germany

Secondary sponsor category [1]

Other Collaborative groups

Name [1]

GenesisCare Clinical CRO Pty Ltd

Address [1]

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Bellberry Human Research Ethics Committee G

Ethics committee address [1]

123 Glen Osmond Road Eastwood South Australia 5063

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

03/04/2024

Approval date [1]

24/05/2024

Ethics approval number [1]

2024-04-420

Summary

Brief summary

The aim of this study is to determine the Optimal Biological Dose, and Evaluate Safety, Pharmacokinetics and Preliminary Efficacy of Actinium (225Ac) Ibu-DAB-PSMA for the Treatment of PSMA-positive Progressive Metastatic Castration Resistant Prostate Cancer

Who is it for?
You may be eligible for this study if you are a Male participant aged at least 18 years have a histologically, pathologically, and/or cytologically confirmed metastatic adenocarcinoma of the prostate without significant sarcomatoid or spindle or neuroendocrine or small cell differentiation components. Stage IV prostate cancer with at least one lesion that is measurable on baseline CT or MRI, or present on bone scan imaging, obtained within 30 days prior to trial enrolment. At least one PSMA PET/CT positive lesion (i.e., higher than liver uptake) within 30 days prior to enrolment.

Study details
Participants will receive different numbers of doses in cycles (two, three, or six), which will test 3 different dose levels/strengths of ITM-22. Participants will then be tested for optimal biological dose, tolerability and safety, preliminary efficacy signals of actinium, pharmacokinetics and biomarkers.

It is hoped that findings from this study will demonstrate that actinium (225Ac) Ibu-DAB-PSMA is safe and well tolerated by patients with progressive mCRPC. The results in this study will determine the optimal biological dose for expansion of the trial in phase 2.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Gary Tincknell

Address

Illawarra Cancer Care Centre, New Dapto Rd, Wollongong, NSW 2500

Country

Australia

Phone

+61 2 4222 5200

Fax

[email protected]

Contact person for public queries

Name

Joseph Su

Address

GenesisCare Clinical CRO Building 7, The Mill, 41-43 Bourke Road Alexandria NSW 2015

Country

Australia

Phone

+61 455 862 083

Fax

[email protected]

Contact person for scientific queries

Name

Frank Fliegert

Address

ITM Oncologics GmbH, Walther-von-Dyck-Strasse 4, 85748 Garching/Munich

Country

Germany

Phone

+49 89 329 8986 6000

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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.

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No additional documents have been identified.

Trial Review

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