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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03746431
Recruitment Status : Recruiting
First Posted : November 19, 2018
Last Update Posted : December 22, 2023
Sponsor:
Information provided by (Responsible Party):
Fusion Pharmaceuticals Inc.

Study Description
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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).

Condition or disease Intervention/treatment Phase
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 Drug: [111In]-FPI-1547 Injection Drug: [225Ac]-FPI-1434 Injection multi-dose Biological: FPI-1175 Infusion Drug: [225Ac]-FPI-1434 Injection single-dose Phase 1 Phase 2

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 253 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Study of [225Ac]-FPI-1434 Injection in Patients With Locally Advanced or Metastatic Solid Tumours
Actual Study Start Date : January 17, 2019
Estimated Primary Completion Date : June 2024
Estimated Study Completion Date : June 2026

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: [225Ac]-FPI-1434 Single-Dose Escalation 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 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.
Experimental: [225Ac]-FPI-1434 Multi-Dose Escalation
[225Ac]-FPI-1434 treatment with or without pre-administration of FPI-1175 (cold antibody).
 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.
Experimental: FPI-1175 Cold Antibody 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.
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).
 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.


Outcome Measures
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Primary Outcome Measures :
  1. Dose Escalation: Incidence of adverse events (AEs). [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
    Phase 1

  2. Single-Dose Escalation: Incidence of dose limiting toxicities (DLTs). [ Time Frame: 8 weeks. ]
    Phase 1

  3. Multi-Dose Escalation: Incidence of DLTs. [ Time Frame: 6 weeks. ]
    Phase 1

  4. Dose Escalation: Incidence of clinically significant clinical laboratory abnormalities. [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
    Phase 1

  5. 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

  6. 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

  7. 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

  8. Evaluate anti-tumour activity of [225Ac]-FPI-1434 regimen [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 injection. ]
    Phase 2

  9. Objective response rate (ORR) RECIST v1.1. [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
    Phase 2


Secondary Outcome Measures :
  1. 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

  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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. Cold Antibody Sub-Study: Incidence of AEs. [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
    Phase 1 and 2

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  21. 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


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03746431


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

Locations
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United States, California
City of Hope Recruiting
Duarte, California, United States, 91010
United States, Massachusetts
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
United States, Minnesota
Masonic Cancer Center, University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
United States, New York
Roswell Park Comprehensive Cancer Center Completed
Buffalo, New York, United States, 14203
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
United States, Pennsylvania
Hospital of the University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Australia, South Australia
Royal Adelaide Hospital Completed
Adelaide, South Australia, Australia, 5000
Australia, Victoria
Austin Hospital Recruiting
Heidelberg, Victoria, Australia, 3084
Canada, Ontario
Juravinski Cancer Center - Hamilton Health Active, not recruiting
Hamilton, Ontario, Canada, L8V 5C2
Princess Margaret Cancer Centre Completed
Toronto, Ontario, Canada, M5G 2C1
Canada, Quebec
Centre Hospitalier De I'Universite de Montreal Recruiting
Montréal, Quebec, Canada, H2X 0C1
Quebec University Hospital- Laval Active, not recruiting
Québec City, Quebec, Canada, G1R 2J6
Sponsors and Collaborators
Fusion Pharmaceuticals Inc.
Investigators
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Study Director: Julia Kazakin, MD Fusion Pharmaceuticals Inc.
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Fusion Pharmaceuticals Inc.
ClinicalTrials.gov Identifier: NCT03746431    
Other Study ID Numbers: FPX-01-01
First Posted: November 19, 2018    Key Record Dates
Last Update Posted: December 22, 2023
Last Verified: December 2023

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Fusion Pharmaceuticals Inc.:
225-Ac Labelled Humanized Monoclonal Antibody Against IGF-1R
[225Ac]-FPI-1434
IGF-IR Targeted Alpha Therapeutic
IGF-IR Radioligand Therapy
Radiopharmaceuticals
Additional relevant MeSH terms:
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Carcinoma
Breast Neoplasms
Endometrial Neoplasms
Triple Negative Breast Neoplasms
Squamous Cell Carcinoma of Head and Neck
Adrenocortical Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Carcinoma, Squamous Cell
Endocrine Gland Neoplasms
Genital Diseases, Female
 Female Urogenital Diseases
Female Urogenital Diseases and Pregnancy Complications
Urogenital Diseases
Genital Neoplasms, Female
Urogenital Neoplasms
Genital Diseases
Endocrine System Diseases
Uterine Neoplasms
Uterine Diseases
Head and Neck Neoplasms
Adenocarcinoma
Adrenal Cortex Neoplasms
Adrenal Gland Neoplasms
Adrenal Cortex Diseases
Adrenal Gland Diseases