A Phase 1/2 Study of [225Ac]-FPI-1434 Injection

• ClinicalTrials.gov Identifier: NCT03746431
• Recruitment Status: Recruiting
• First Posted: November 19, 2018
• Last Update Posted: December 22, 2023
• Sponsor: Fusion Pharmaceuticals Inc.
• Information provided by (Responsible Party): Fusion Pharmaceuticals Inc.

Tracking Information

• First Submitted Date: November 9, 2018
• First Posted Date: November 19, 2018
• Last Update Posted Date: December 22, 2023
• Actual Study Start Date: January 17, 2019
• Estimated Primary Completion Date: June 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 27, 2022)

• Dose Escalation: Incidence of adverse events (AEs). [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
  Phase 1
• Single-Dose Escalation: Incidence of dose limiting toxicities (DLTs). [ Time Frame: 8 weeks. ]
  Phase 1
• Multi-Dose Escalation: Incidence of DLTs. [ Time Frame: 6 weeks. ]
  Phase 1
• Dose Escalation: Incidence of clinically significant clinical laboratory abnormalities. [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
  Phase 1
• Dose Escalation: Changes in electrocardiogram (ECG) parameters (PR, QRS, QT, and QTc intervals). [ Time Frame: 4 weeks post final [225Ac]-FPI-1434 Injection. ]
  Phase 1
• Cold Antibody Sub-Study: Changes in uptake of [111In]-FPI-1547 Injection following FPI-1175 Infusion in selected regions of interest on SPECT/CT images. [ Time Frame: Within two weeks of the first [111In]-FPI-1547 Injection. ]
  Phase 1
• Cold Antibody Sub-Study: Changes in radiation dose estimates for selected tissues, organs and whole body both for [111In]-FPI-1547 and [225Ac]-FPI-1434 Injection at various dose levels following FPI-1175 Infusion. [ Time Frame: Within two weeks of the first [111In]-FPI-1547 Injection. ]
  Phase 1
• Evaluate anti-tumour activity of [225Ac]-FPI-1434 regimen [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 injection. ]
  Phase 2
• Objective response rate (ORR) RECIST v1.1. [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
  Phase 2

• Original Primary Outcome Measures (submitted: November 15, 2018): Frequency and severity of adverse events [ Time Frame: 56 days. ]

Current Secondary Outcome Measures (submitted: October 27, 2022)

• Dose Escalation and Cold Antibody Sub-Study: Tumour uptake of [111In]-FPI-1547 in selected regions of interest on SPECT/CT images. [ Time Frame: Dose Escalation: Within one week of the [111In]-FPI-1547 Injection. Cold-Antibody Sub-Study: Within two weeks of the first [111In]-FPI-1547 Injection. ]
  Phase 1 and 2
• Dose Escalation: Radiation doses for selected organs and whole body both for [111In]-FPI-1547 Injection and [225Ac]-FPI-1434 Injection. [ Time Frame: Within one week of the [111In]-FPI-1547 Injection. ]
  Phase 1 and 2
• Dose Escalation and Cold-Antibody Sub-Study: Changes in radiation absorbed doses for tumour lesions for [225Ac]-FPI-1434. [ Time Frame: Dose Escalation: Within one week of the [111In]-FPI-1547 Injection. Cold-Antibody Sub-Study: Within two weeks of the first [111In]-FPI-1547 Injection. ]
  Phase 1 and 2
• Dose Escalation and Cold-Antibody Sub-Study: Clearance for radioactivity and for the targeting antibody. [ Time Frame: 4 weeks post final [225Ac]-FPI-1434 Injection. ]
  Phase 1 and 2
• Dose Escalation and Cold-Antibody Sub-Study: Area under the curve (AUC) for radioactivity and for the targeting antibody. [ Time Frame: 4 weeks post final [225Ac]-FPI-1434 Injection. ]
  Phase 1 and 2
• Dose Escalation and Cold-Antibody Sub-Study: Cmax for radioactivity and for the targeting antibody. [ Time Frame: 4 weeks post final [225Ac]-FPI-1434 Injection. ]
  Phase 1 and 2
• Dose Escalation and Cold-Antibody Sub-Study: Half-life for radioactivity and for the targeting antibody. [ Time Frame: 4 weeks post final [225Ac]-FPI-1434 Injection. ]
  Phase 1 and 2
• Dose Escalation and Cold-Antibody Sub-Study: Objective response rate (ORR) (sum of complete and partial response) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Prostate Cancer Working Group 3 (PCWG3) guidelines. [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
  Phase 1
• Dose Escalation: Changes in the corrected QT (QTc) interval in milliseconds after [225Ac]-FPI-1434 treatment, compared to baseline. [ Time Frame: Approximately 24 hours from the time of [225Ac]-FPI-1434 Injection administration. ]
  Phase 1 and 2
• Dose Escalation and Cold-Antibody Sub-Study: Changes in human growth hormone (hGh) following [111In]-FPI-1547 Injection and [225Ac]-FPI-1434 Injection. [ Time Frame: 4 weeks post final [225Ac]-FPI-1434 Injection. ]
  Phase 1 and 2
• Dose Escalation and Cold-Antibody Sub-Study: Changes in insulin-like growth factor 1 (IGF-1) following [111In]-FPI-1547 Injection and [225Ac]-FPI-1434 Injection. [ Time Frame: 4 weeks post final [225Ac]-FPI-1434 Injection. ]
  Phase 1 and 2
• Dose Escalation and Cold-Antibody Sub-Study: Changes in insulin-like growth factor binding protein 3 (IGFBP-3) following [111In]-FPI-1547 Injection and [225Ac]-FPI-1434 Injection. [ Time Frame: 4 weeks post final [225Ac]-FPI-1434 Injection. ]
  Phase 1 and 2
• Cold Antibody Sub-Study: Incidence of AEs. [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
  Phase 1 and 2
• Cold Antibody Sub-Study: Incidence of clinically significant clinical laboratory abnormalities. [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
  Phase 1 and 2
• Cold Antibody Sub-Study: Changes in ECG parameters (PR, QRS, QT, and QTc intervals). [ Time Frame: 4 weeks post final [225Ac]-FPI-1434 Injection. ]
  Phase 1 and 2
• Dose Escalation and Cold-Antibody Sub-Study: Time to response (TTR). [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
  Phase 1 and 2
• Dose Escalation and Cold-Antibody Sub-Study: Duration of response (DoR). [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
  Phase 1 and 2
• Dose Escalation and Cold-Antibody Sub-Study: Progression free survival (PFS). [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
  Phase 1 and 2
• Dose Escalation and Cold-Antibody Sub-Study: Time to Progression (TTP). [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
  Phase 1 and 2
• Dose Escalation and Cold-Antibody Sub-Study: Disease control rate (DCR). [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
  Phase 1 and 2
• Dose Escalation and Cold-Antibody Sub-Study: Overall survival (OS). [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
  Phase 1 and 2

Original Secondary Outcome Measures (submitted: November 15, 2018)

• Tumour uptake of [111In]-FPI-1547 Injection in selected regions of interest on SPECT/CT images. [ Time Frame: Within one week of the 111In]-FPI-1547 Injection. ]
• Radiation doses for selected organs and whole body both for [111In]-FPI-1547 and [225Ac]-FPI-1434. [ Time Frame: Three months. ]
• Radiation doses for tumour lesions for [225Ac]-FPI-1434. [ Time Frame: Three months. ]
• Clearance for radioactivity and for the targeting antibody. [ Time Frame: Three months. ]
• Area under the curve (AUC) for radioactivity and for the targeting antibody. [ Time Frame: Three months. ]
• Cmax for radioactivity and for the targeting antibody. [ Time Frame: Three months. ]
• Half-life for radioactivity and for the targeting antibody. [ Time Frame: Three months. ]
• Objective response rate (sum of complete and partial response) per RECIST 1.1 or PCWG3 guidelines, duration of response and progression free survival. [ Time Frame: Approximately one year. ]
• Changes in the QTc interval in milliseconds after [225Ac]-FPI-1434 treatment, compared to baseline. [ Time Frame: Approximately 24 hours from the time of [225Ac]-FPI-1434 Injection administration. ]
• Changes in human growth hormone (hGh), insulin-like growth factor (IGF)-1 and insulin-like growth binding protein 3 (IGFBP-3) following [111In]-FPI-1547 and [225Ac]-FPI-1434 injections. [ Time Frame: 56 days. ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase 1/2 Study of [225Ac]-FPI-1434 Injection
• Official Title: A Phase 1/2 Study of [225Ac]-FPI-1434 Injection in Patients With Locally Advanced or Metastatic Solid Tumours
• Brief Summary: This is a first-in-human Phase 1/2, non-randomized, multi-centre, open-label clinical study designed to investigate safety, tolerability, PK, and preliminary anti-tumour activity of [225Ac]-FPI-1434 (radioimmuno-therapeutic agent) in patients with solid tumours that demonstrate uptake of [111In]-FPI-1547 (radioimmuno-imaging agent), and to establish the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of repeat doses of [225Ac]-FPI-1434 Injection in patients with solid tumours that demonstrate uptake of [111In]-FPI-1547 (radioimmuno-imaging agent).

Detailed Description

This study consists of a Phase 1 portion and a Phase 2 portion.

Phase 1 includes the following cohorts: Single dose-ascending cohorts and Multi- dose ascending cohorts of [225Ac]-FPI-1434 and Multi- dose ascending cohorts evaluating administration of FPI-1175 (cold antibody), followed by, [225Ac]-FPI-1434 (cold + hot), with cycles repeating every 42 days. And Cold Antibody Sub-study evaluating administration of ascending doses of FPI-1175 followed by [111In]-FPI-1547.

The Phase 2 will evaluate [111In]-FPI-1547 and [225Ac]-FPI-1434 with or without FPI-1175 in tumour-specific cohorts. The decision to utilize FPI-1175 in the Phase 2 portion of the study will be determined based on Phase 1 data, including safety, tolerability, pharmacokinetic and dosimetry results.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Advanced Solid Tumours
• Endometrial Cancer
• Cervical Cancer
• Ovarian Cancer
• Breast Cancer
• Triple Negative Breast Cancer (TNBC)
• HER2-negative Breast Cancer
• Head and Neck Squamous Cell Carcinoma (HNSCC)
• Adrenocortical Carcinoma
• Uveal Melanoma

Intervention

• Drug: [111In]-FPI-1547 Injection
  [111In]-FPI-1547 is a targeted radioimmuno-imaging agent that consists of FPI-1175, an insulin-like growth factor-1 receptor (IGF-1R)-targeting humanized monoclonal antibody, a bifunctional chelate, and Indium-111, a radionuclide. Patients will receive [111In]-FPI-1547 Injection of 185 MBq (5 mCi) for imaging.
• Drug: [225Ac]-FPI-1434 Injection multi-dose
  [225Ac]-FPI-1434 is a targeted alpha radioimmuno-therapeutic agent that consists of FPI-1175, an insulin-like growth factor-1 receptor (IGF-1R)-targeting humanized monoclonal antibody, a bifunctional chelate, and Actinium-225, an alpha-emitting radionuclide. Patients will receive multiple doses of [225Ac]-FPI-1434 Injection. Dose is per cohort assignment.
• Biological: FPI-1175 Infusion
  FPI-1175 is an insulin-like growth factor-1 receptor (IGF-1R)-targeting humanized monoclonal antibody without a radioisotope. Patients will receive FPI-1175 Infusion at a dose per cohort assignment.
• Drug: [225Ac]-FPI-1434 Injection single-dose
  [225Ac]-FPI-1434 is a targeted alpha radioimmuno-therapeutic agent that consists of FPI-1175, an insulin-like growth factor-1 receptor (IGF-1R)-targeting humanized monoclonal antibody, a bifunctional chelate, and Actinium-225, an alpha-emitting radionuclide. Patients will receive a single dose of [225]-FPI-1434 Injection. Dose is per cohort assignment.

Study Arms

• Experimental: [225Ac]-FPI-1434 Single-Dose Escalation
  Interventions:

  • Drug: [111In]-FPI-1547 Injection
  • Drug: [225Ac]-FPI-1434 Injection single-dose
• Experimental: [225Ac]-FPI-1434 Multi-Dose Escalation
  [225Ac]-FPI-1434 treatment with or without pre-administration of FPI-1175 (cold antibody).
  Interventions:

  • Drug: [111In]-FPI-1547 Injection
  • Drug: [225Ac]-FPI-1434 Injection multi-dose
  • Biological: FPI-1175 Infusion
• Experimental: FPI-1175 Cold Antibody
  Interventions:

  • Drug: [111In]-FPI-1547 Injection
  • Drug: [225Ac]-FPI-1434 Injection multi-dose
  • Biological: FPI-1175 Infusion
• Experimental: [225Ac]-FPI-1434 Multi-Dose
  Phase 2 Tumour Cohort - Head & Neck Squamous Cell Carcinoma (HNSCC), Endometrial Cancer, Cervical Cancer, Ovarian Cancer, Triple Negative Breast Cancer (TNBC), HER2-negative, Adrenocortical Carcinoma (ACC), Uveal Melanoma, [225Ac]-FPI-1434 treatment with or without pre-administration of FPI-1175 (cold antibody).
  Interventions:

  • Drug: [111In]-FPI-1547 Injection
  • Drug: [225Ac]-FPI-1434 Injection multi-dose
  • Biological: FPI-1175 Infusion

• Publications *: Martiniova L, Zielinski RJ, Lin M, DePalatis L, Ravizzini GC. The Role of Radiolabeled Monoclonal Antibodies in Cancer Imaging and ADC Treatment. Cancer J. 2022 Nov-Dec 01;28(6):446-453. doi: 10.1097/PPO.0000000000000625.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 27, 2022): 253
• Original Estimated Enrollment (submitted: November 15, 2018): 30
• Estimated Study Completion Date: June 2026
• Estimated Primary Completion Date: June 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Pathologically documented, definitively diagnosed, advanced solid tumour that is refractory to all standard treatment, for which no standard treatment is available, or it is contraindicated, or the patient refuses standard therapy.
2. Measurable or evaluable disease in accordance with RECIST 1.1.
3. Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1.
4. Life expectancy of greater than 3 months as judged by the treating physician.
5. Available tumour tissue (either archival or fresh biopsy) for IGF-1R immunohistochemistry. Submission of the tissue is not required prior to enrollment.
6. Adequate heart, kidney, and liver function
7. Adequate bone marrow reserves

8. Ability to understand and the willingness to sign a written informed consent document.

   Phase 2 Specific

9. Histologically and/or cytologically documented diagnosis of locally advanced, inoperable, metastatic, or recurrent solid tumour types: endometrial, cervical, ovarian, TNBC, HER 2-negative breast, HNSCC, ACC, or uveal melanoma.

10. Have measurable disease per RECIST 1.1 Failure to respond to standard systemic therapy, or for whom standard or curative systemic therapy does not exist or is not tolerable.

    Imaging Eligibility

11. Prior to the initial [225Ac]-FPI-1434 cycle: Sufficient target expression in at least 1 lesion following [111In]-FPI-1547 and SPECT imaging.

Exclusion Criteria:

1. Systemic therapeutic radiopharmaceutical within 6 months prior to enrollment into this study.
2. Contraindications to or inability to perform the required imaging procedures in this study (e.g., inability to lay flat during scan time)
3. Uncontrolled brain metastasis, including but not limited to the need for treatment with steroids, surgery or radiation therapy.
4. Anticancer therapy (including investigational agents) or external beam radiation therapy within 14 days of the dosing of [111In]-FPI-1547
5. Has known additional malignancy that is progressing or has required active treatment within the past 3 years. Patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ (e.g., breast cancer, cervical cancer, prostate) that have undergone potentially curative therapy are not excluded.
6. Residual CTCAE ≥ Grade 2 side effects of prior therapy, with the exception of residual grade 2 alopecia.
7. Prior organ transplantation, including stem cell transplantation.
8. Any prior treatment with nitrosoureas or actinomycin-D.
9. Clinically relevant levels of protein in the urine
10. Known or suspected allergies or contraindications to the Investigational Products or any component of the investigational drug formulation.
11. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, diabetes, or psychiatric illness/social situations that would limit compliance with study requirements.
12. Received > 20 Gy prior radiation to large areas of the bone marrow

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: clinicaltrials@fusionpharma.com; +1 (888) 506-4215; clinicaltrials@fusionpharma.com

• Listed Location Countries: Australia, Canada, United States

Administrative Information

• NCT Number: NCT03746431
• Other Study ID Numbers: FPX-01-01
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Fusion Pharmaceuticals Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Fusion Pharmaceuticals Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Julia Kazakin, MD; Fusion Pharmaceuticals Inc.

• PRS Account: Fusion Pharmaceuticals Inc.
• Verification Date: December 2023