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

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ClinicalTrials.gov Identifier: NCT03746431
Recruitment Status : Recruiting
First Posted : November 19, 2018
Last Update Posted : May 4, 2021
Sponsor:
Information provided by (Responsible Party):
Fusion Pharmaceuticals Inc.

Brief Summary:
This is a first-in-human phase 1, non-randomized, multi-centre, open-label clinical trial designed to investigate safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumour activity of [111In]-FPI-1547 Injection (radioimmuno-imaging agent) and [225Ac]-FPI-1434 Injection (radioimmuno-therapeutic) 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. The study consists of a dose escalation portion, including both single and multi-dosing cohorts, of approximately five cohorts and a cold antibody sub-study portion of up to three cohorts.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumours Actinium-225 Antineoplastic Agents Targeted Alpha Therapy Radioimmunoconjugate 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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 38 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Study of [225Ac]-FPI-1434 Injection in Patients With Advanced Solid Tumours
Actual Study Start Date : January 17, 2019
Estimated Primary Completion Date : April 2022
Estimated Study Completion Date : December 2022

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 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 [225]-FPI-1434 Injection. Dose is 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 [225]-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. Patients will receive FPI-1175 Infusion at a dose per cohort assignment.




Primary Outcome Measures :
  1. Dose Escalation: Incidence of adverse events (AEs). [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
  2. Single-Dose Escalation: Incidence of dose limiting toxicities (DLTs). [ Time Frame: 8 weeks. ]
  3. Multi-Dose Escalation: Incidence of DLTs. [ Time Frame: 6 weeks. ]
  4. Dose Escalation: Incidence of clinically significant clinical laboratory abnormalities. [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
  5. Dose Escalation: Changes in electrocardiogram (ECG) parameters (PR, QRS, QT, and QTc intervals). [ Time Frame: 4 weeks post final [225Ac]-FPI-1434 Injection. ]
  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. ]
  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. ]

Secondary Outcome Measures :
  1. Dose Escalation and Cold Antibody Sub-Study: Tumour uptake of [111In]-FPI-1547 Injection 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. ]
  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. ]
  3. Dose Escalation and Cold-Antibody Sub-Study: Radiation doses for tumour lesions for [225Ac]-FPI-1434 Injection. [ 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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  13. Cold Antibody Sub-Study: Incidence of AEs. [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
  14. Cold Antibody Sub-Study: Incidence of clinically significant clinical laboratory abnormalities. [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
  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. ]
  16. Dose Escalation and Cold-Antibody Sub-Study: Time to response (TTR). [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
  17. Dose Escalation and Cold-Antibody Sub-Study: Duration of response (DoR). [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
  18. Dose Escalation and Cold-Antibody Sub-Study: Progression free survival (PFS). [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
  19. Dose Escalation and Cold-Antibody Sub-Study: Time to Progression (TTP). [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
  20. Dose Escalation and Cold-Antibody Sub-Study: Disease control rate (DCR). [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
  21. Dose Escalation and Cold-Antibody Sub-Study: Overall survival (OS). [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]

Other Outcome Measures:
  1. Dose Escalation: Correlation of uptake of [111In]-FPI-1547 with observed toxicities following therapeutic administration of [225Ac]-FPI-1434 Injection. [ Time Frame: Approximately one year post final [225Ac]-FPI-1434 Injection. ]
  2. Dose Escalation: Correlation of uptake of [111In]-FPI-1547 with biomarker results (e.g., immunohistochemistry (ICH) staining, [18F]-FDG Positron Emission Tomography (PET)). [ Time Frame: 4 weeks post final [225Ac]-FPI-1434 Injection. ]


Information from the National Library of Medicine

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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. Age ≥18 years old.
  2. 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.
  3. At least 2 measurable lesions: one of which is at least ≥ 20 mm in largest diameter.
  4. Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1.
  5. Life expectancy of ≥ 3 months as judged by the treating physician.
  6. Available tumour tissue (either archival or fresh biopsy) for IGF-1R immunohistochemistry. Submission of the tissue is not required prior to enrollment.
  7. Adequate bone marrow reserves without the use of hematopoietic growth factors, red cell or platelet transfusion as evidenced by:

    1. Absolute neutrophil count ≥ 1,500/ mm^3 (≥ 1.5 x 10^9/L)
    2. Platelet count ≥ 100,000/ mm^3 (≥ 100 x 10^9/L)
    3. Hemoglobin ≥ 9 g/dL (≥ 90 g/L)
  8. Adequate renal function as evidenced by a creatinine clearance ≥ 60 mL/min using the Cockcroft-Gault Equation. Actual body weight should be used for calculating creatinine clearance using the Cockcroft-Gault Equation.
  9. Adequate hepatic function as evidenced by:

    1. Serum total bilirubin ≤ 1.5x upper limit of normal (ULN), unless patient has Gilbert's disease
    2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN (≤ 5 x ULN in patients with known liver metastasis)
  10. Other laboratory results, vital signs and ECG are judged by the Investigator to be acceptable for enrollment into the study.
  11. Females of childbearing potential must have a negative pregnancy test result during screening.
  12. Females of childbearing potential and all men must agree to use at least two highly effective forms of contraception one of which must be a barrier method, or agree to remain abstinent, for the duration of study participation and 28 days following the [111In]-FPI-1547 injection, and 5 months (for males) or 8 months (for females)following the final [225Ac]-FPI-1434 Injection.
  13. Ability to understand and the willingness to sign a written informed consent document.
  14. In the judgement of the Investigator, the patient is expected to be compliant and have a high probability of completing the study.

Exclusion Criteria:

  1. Received a 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 for the image acquisitions, etc.)
  3. Uncontrolled brain metastasis, including but not limited to need for treatment with steroids, surgery or radiation therapy.
  4. Anticancer therapy (including investigations agents) or external beam radiation therapy within 14 days of the dosing of [111In]-FPI-1547 (6 weeks for mitomycin-C). Ongoing androgen deprivation therapy for prostate cancer, thyroid stimulating hormone suppression for differentiated thyroid cancer, somatostatin analogues for neuroendocrine tumors are NOT considered exclusion criteria.
  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. Residual Common Terminology Criteria for Adverse Events (CTCAE) ≥ Grade 2 side effects of any therapy mentioned above, with the exception of residual grade 2 alopecia.
  6. Prior organ transplantation, including stem cell transplantation.
  7. Any prior treatment with nitrosoureas or actinomycin-D.
  8. Clinical relevant proteinuria (e.g. urinary dipstick analysis for proteins is 3+ [300 mg/dL or 4+ [1,000 mg/dL], or daily urinary protein excretion > 500 mg/dL).
  9. Known or suspect allergies or contraindications to the Investigational Products or any component of the investigational drug formulation.
  10. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, diabetes (random blood sugar during screening ≥250 mg/dL [≥ 13.9 mmol/L]), or psychiatric illness/social situations that would limit compliance with study requirements.
  11. Received > 20 Gy prior radiation to large areas of the bone marrow (e.g. external radiation therapy to whole pelvis)

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: Lauren Creeden, BS 1-888-506-4215 ext 203 creeden@fusionpharma.com

Locations
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United States, Massachusetts
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
United States, New York
Roswell Park Comprehensive Cancer Center Recruiting
Buffalo, New York, United States, 14203
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 Not yet recruiting
Houston, Texas, United States, 77030
Australia, South Australia
Royal Adelaide Hospital Recruiting
Adelaide, South Australia, Australia, 5000
Australia, Victoria
Austin Hospital Recruiting
Heidelberg, Victoria, Australia, 3084
Canada, Ontario
Juravinski Cancer Center - Hamilton Health Recruiting
Hamilton, Ontario, Canada, L8V 5C2
Princess Margaret Cancer Centre Recruiting
Toronto, Ontario, Canada, M5G 2C1
Canada, Quebec
Centre Hospitalier De I'Universite de Montreal Recruiting
Montréal, Quebec, Canada, H2X 0C1
Quebec University Hospital- Laval Recruiting
Québec City, Quebec, Canada, G1R 2J6
Sponsors and Collaborators
Fusion Pharmaceuticals Inc.
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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: May 4, 2021
Last Verified: May 2021

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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