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

Breast Cancer Clinical Trial

Official title:

A Phase 1/2 Study of [225Ac]-FPI-1434 Injection in Patients With Locally Advanced or Metastatic Solid Tumours

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03746431
• Other study ID #: FPX-01-01
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: January 17, 2019
• Est. completion date: June 2026

Study information

• Verified date: December 2023
• Source: Fusion Pharmaceuticals Inc.
• Contact: clinicaltrials@fusionpharma.com
• Phone: +1 (888) 506-4215
• Email: clinicaltrials[@]fusionpharma.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 253
• Est. completion date: June 2026
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

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

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Austin Hospital	Heidelberg	Victoria
Canada	Juravinski Cancer Center - Hamilton Health	Hamilton	Ontario
Canada	Centre Hospitalier De I'Universite de Montreal	Montréal	Quebec
Canada	Quebec University Hospital- Laval	Québec City	Quebec
Canada	Princess Margaret Cancer Centre	Toronto	Ontario
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Roswell Park Comprehensive Cancer Center	Buffalo	New York
United States	City of Hope	Duarte	California
United States	University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Masonic Cancer Center, University of Minnesota	Minneapolis	Minnesota
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Fusion Pharmaceuticals Inc.

Countries where clinical trial is conducted

United States,  Australia,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose Escalation: Incidence of adverse events (AEs).	Phase 1	Approximately one year post final [225Ac]-FPI-1434 Injection.
Primary	Single-Dose Escalation: Incidence of dose limiting toxicities (DLTs).	Phase 1	8 weeks.
Primary	Multi-Dose Escalation: Incidence of DLTs.	Phase 1	6 weeks.
Primary	Dose Escalation: Incidence of clinically significant clinical laboratory abnormalities.	Phase 1	Approximately one year post final [225Ac]-FPI-1434 Injection.
Primary	Dose Escalation: Changes in electrocardiogram (ECG) parameters (PR, QRS, QT, and QTc intervals).	Phase 1	4 weeks post final [225Ac]-FPI-1434 Injection.
Primary	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.	Phase 1	Within two weeks of the first [111In]-FPI-1547 Injection.
Primary	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.	Phase 1	Within two weeks of the first [111In]-FPI-1547 Injection.
Primary	Evaluate anti-tumour activity of [225Ac]-FPI-1434 regimen	Phase 2	Approximately one year post final [225Ac]-FPI-1434 injection.
Primary	Objective response rate (ORR) RECIST v1.1.	Phase 2	Approximately one year post final [225Ac]-FPI-1434 Injection.
Secondary	Dose Escalation and Cold Antibody Sub-Study: Tumour uptake of [111In]-FPI-1547 in selected regions of interest on SPECT/CT images.	Phase 1 and 2	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.
Secondary	Dose Escalation: Radiation doses for selected organs and whole body both for [111In]-FPI-1547 Injection and [225Ac]-FPI-1434 Injection.	Phase 1 and 2	Within one week of the [111In]-FPI-1547 Injection.
Secondary	Dose Escalation and Cold-Antibody Sub-Study: Changes in radiation absorbed doses for tumour lesions for [225Ac]-FPI-1434.	Phase 1 and 2	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.
Secondary	Dose Escalation and Cold-Antibody Sub-Study: Clearance for radioactivity and for the targeting antibody.	Phase 1 and 2	4 weeks post final [225Ac]-FPI-1434 Injection.
Secondary	Dose Escalation and Cold-Antibody Sub-Study: Area under the curve (AUC) for radioactivity and for the targeting antibody.	Phase 1 and 2	4 weeks post final [225Ac]-FPI-1434 Injection.
Secondary	Dose Escalation and Cold-Antibody Sub-Study: Cmax for radioactivity and for the targeting antibody.	Phase 1 and 2	4 weeks post final [225Ac]-FPI-1434 Injection.
Secondary	Dose Escalation and Cold-Antibody Sub-Study: Half-life for radioactivity and for the targeting antibody.	Phase 1 and 2	4 weeks post final [225Ac]-FPI-1434 Injection.
Secondary	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.	Phase 1	Approximately one year post final [225Ac]-FPI-1434 Injection.
Secondary	Dose Escalation: Changes in the corrected QT (QTc) interval in milliseconds after [225Ac]-FPI-1434 treatment, compared to baseline.	Phase 1 and 2	Approximately 24 hours from the time of [225Ac]-FPI-1434 Injection administration.
Secondary	Dose Escalation and Cold-Antibody Sub-Study: Changes in human growth hormone (hGh) following [111In]-FPI-1547 Injection and [225Ac]-FPI-1434 Injection.	Phase 1 and 2	4 weeks post final [225Ac]-FPI-1434 Injection.
Secondary	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.	Phase 1 and 2	4 weeks post final [225Ac]-FPI-1434 Injection.
Secondary	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.	Phase 1 and 2	4 weeks post final [225Ac]-FPI-1434 Injection.
Secondary	Cold Antibody Sub-Study: Incidence of AEs.	Phase 1 and 2	Approximately one year post final [225Ac]-FPI-1434 Injection.
Secondary	Cold Antibody Sub-Study: Incidence of clinically significant clinical laboratory abnormalities.	Phase 1 and 2	Approximately one year post final [225Ac]-FPI-1434 Injection.
Secondary	Cold Antibody Sub-Study: Changes in ECG parameters (PR, QRS, QT, and QTc intervals).	Phase 1 and 2	4 weeks post final [225Ac]-FPI-1434 Injection.
Secondary	Dose Escalation and Cold-Antibody Sub-Study: Time to response (TTR).	Phase 1 and 2	Approximately one year post final [225Ac]-FPI-1434 Injection.
Secondary	Dose Escalation and Cold-Antibody Sub-Study: Duration of response (DoR).	Phase 1 and 2	Approximately one year post final [225Ac]-FPI-1434 Injection.
Secondary	Dose Escalation and Cold-Antibody Sub-Study: Progression free survival (PFS).	Phase 1 and 2	Approximately one year post final [225Ac]-FPI-1434 Injection.
Secondary	Dose Escalation and Cold-Antibody Sub-Study: Time to Progression (TTP).	Phase 1 and 2	Approximately one year post final [225Ac]-FPI-1434 Injection.
Secondary	Dose Escalation and Cold-Antibody Sub-Study: Disease control rate (DCR).	Phase 1 and 2	Approximately one year post final [225Ac]-FPI-1434 Injection.
Secondary	Dose Escalation and Cold-Antibody Sub-Study: Overall survival (OS).	Phase 1 and 2	Approximately one year post final [225Ac]-FPI-1434 Injection.