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A Study of LOXO-435 in Participants With Cancer With a Change in a Gene Called FGFR3

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: NCT05614739
Recruitment Status : Recruiting
First Posted : November 14, 2022
Last Update Posted : April 5, 2024
Sponsor:
Collaborators:
Loxo Oncology, Inc.
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):
Eli Lilly and Company

Study Description
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Brief Summary:
The main purpose of this study is to learn more about the safety, side effects, and effectiveness of LOXO-435. LOXO-435 may be used to treat cancer of the cells that line the urinary system and other solid tumor cancers that have a change in a particular gene (known as the FGFR3 gene). Participation could last up to 30 months (2.5 years) and possibly longer if the disease does not get worse.

Condition or disease Intervention/treatment Phase
Urinary Bladder Neoplasms Neoplasm Metastasis Ureteral Neoplasms Drug: LOXO-435 Drug: Pembrolizumab Phase 1

Detailed Description:
This is an open-label, multi-center, phase 1a/b study in participants with FGFR3-altered advanced solid tumors, including metastatic urothelial cancer (UC). The study will be conducted in 2 phases: Dose escalation and dose optimization (1a) and dose expansion (1b). Phase 1a will include up to 2 cohorts to assess safety, tolerability, and pharmacokinetics of LOXO-435 to determine the recommended phase 2 dose (RP2D) (or optimal dose). Phase 1b will include 4 dose expansion cohorts of participants with prespecified activating FGFR3 alterations to evaluate the efficacy and safety of LOXO-435 at the RP2D. Cohort B will enroll pts with metastatic UC and includes three cohorts to evaluate LOXO-435 as monotherapy (B1, B2) and in combination with pembrolizumab (B3). Cohort C will enroll pts with non-UC advanced solid tumors and includes a cohort to evaluate LOXO-435 as monotherapy (C1).
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 180 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label, Multicenter Study of LOXO-435 (LY3866288) In Advanced Solid Tumor Malignancies With FGFR3 Alterations
Actual Study Start Date : January 12, 2023
Estimated Primary Completion Date : June 2025
Estimated Study Completion Date : June 2025

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Phase 1a: Cohort A1 LOXO-435 Monotherapy Dose Escalation
LOXO-435 administered orally to participants with FGFR3-altered advanced solid tumors.
 Drug: LOXO-435
Oral
Other Name: LY3866288
Experimental: Phase 1a: Cohort A2 LOXO-435 Monotherapy Dose Optimization
LOXO-435 administered orally to participants with FGFR3-altered advanced urothelial carcinoma. (Cohort to be implemented as needed, based on Sponsor's discretion.)
 Drug: LOXO-435
Oral
Other Name: LY3866288
Experimental: Phase 1b: Cohort B1 LOXO-435 Monotherapy Dose Expansion
LOXO-435 administered orally to participants with FGFR3-altered advanced urothelial carcinoma who were previously treated with an FGFR inhibitor.
 Drug: LOXO-435
Oral
Other Name: LY3866288
Experimental: Phase 1b: Cohort B2 LOXO-435 Monotherapy Dose Expansion
LOXO-435 administered orally to participants with FGFR3-altered advanced urothelial carcinoma who have not received a prior FGFR inhibitor.
 Drug: LOXO-435
Oral
Other Name: LY3866288
Experimental: Phase 1b: Cohort B3 LOXO-435 Plus Pembrolizumab
LOXO-435 administered orally in combination with pembrolizumab administered intravenously (IV) to participants with FGFR3-altered advanced urothelial carcinoma who have not received a prior FGFR inhibitor.
 Drug: LOXO-435
Oral
Other Name: LY3866288

Drug: Pembrolizumab
IV
Other Name: KEYTRUDA®
Experimental: Phase 1b: Cohort C1 LOXO-435 Monotherapy Dose Expansion
LOXO-435 administered orally to participants with advanced solid tumors who have not received a prior FGFR inhibitor.
 Drug: LOXO-435
Oral
Other Name: LY3866288


Outcome Measures
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Primary Outcome Measures :
  1. Phase 1a: To determine the recommended phase 2 dose (RP2D)/optimal dose of LOXO-435: Safety, number of participants with dose-limiting toxicities (DLTs) [ Time Frame: Minimum of the first 21-day cycle of LOXO-435 treatment ]
    Number of participants with DLTs

  2. Phase 1b: To evaluate the preliminary antitumor activity of LOXO-435: Overall response rate (ORR) [ Time Frame: Up to approximately 30 months or 2.5 years ]
    ORR per investigator assessed RECIST v1.1


Secondary Outcome Measures :
  1. To assess the pharmacokinetics (PK) of LOXO-435: Area under the concentration versus time curve (AUC) [ Time Frame: Up to 2 months ]
    PK of LOXO-435: AUC

  2. To assess the PK of LOXO-435: Minimum plasma concentration (Cmin) [ Time Frame: Up to 2 months ]
    PK of LOXO-435: Cmin

  3. To evaluate the preliminary antitumor activity of LOXO-435: Duration of response (DoR) [ Time Frame: Up to approximately 30 months or 2.5 years ]
    DOR per investigator assessed RECIST 1.1

  4. To evaluate the preliminary antitumor activity of LOXO-435: Time to response (TTR) [ Time Frame: Up to approximately 30 months or 2.5 years ]
    TTR

  5. To evaluate the preliminary antitumor activity of LOXO-435: Progression-free survival (PFS) [ Time Frame: Up to approximately 30 months or 2.5 years ]
    PFS per investigator assessed RECIST 1.1

  6. To evaluate the preliminary antitumor activity of LOXO-435: Disease control rate (DCR) [ Time Frame: Up to approximately 30 months or 2.5 years ]
    DCR per investigator assessed RECIST 1.1

  7. To evaluate the preliminary antitumor activity of LOXO-435: Overall survival (OS) [ Time Frame: Up to approximately 30 months or 2.5 years ]
    OS

  8. Change from baseline in bladder-related symptoms, measured by Functional Assessment of Cancer Therapy - Bladder (FACT-Bl) subscale (BlCS) [ Time Frame: Cycle 1 Day 1, Cycle 2 Day 1, and Cycle 3 Day 1 (28 day cycles) ]
    The BlCS has 12 items with a total score range of 0 to 48, with higher scores representing better bladder-related symptoms. A ≥ 4-point score change from baseline will be considered as clinically meaningful improvement in bladder-related symptoms

  9. Change from baseline in physical function, measured by FACT- Physical Well-being Scale (PWB) subscale [ Time Frame: Up to approximately 30 months or 2.5 years ]
    The PWB subscale has 7 items with a total score range of 0-28, with higher scores representing better physical function. A ≥ 3-point score change from baseline for a participant will be considered as clinically meaningful improvement in physical function.


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:

  • Have solid tumor cancer with an FGFR3 pathway alteration on molecular testing in tumor or blood sample that is deemed as actionable.

    • Cohort A1 (Dose Escalation): Presence of an alteration in FGFR3 or its ligands.
    • Cohort A2 (Dose Optimization): Histological diagnosis of urothelial cancer (UC) that is locally advanced or metastatic with a qualifying FGFR3 alteration.
    • Cohorts B1, B2 and B3 (Dose Expansion): Histological diagnosis of urothelial cancer that is locally advanced or metastatic with a prespecified activating FGFR3 alteration.
    • Cohort C (Dose Expansion): Must have histological diagnosis of a non-urothelial solid tumor malignancy that is locally advanced or metastatic with a prespecified activating FGFR3 alteration.

  • Measurability of disease:

    • Cohort A1: Measurable or non-measurable disease as defined by Response Evaluation Criteria in Solid Tumors v 1.1 (RECIST v1.1)
    • Cohorts A2, B1, B2, B3, and C1: Measurable disease required as defined by RECIST v1.1
  • Have adequate archival tumor tissue sample available or undergo a screening biopsy if allowed per country-specific regulations.
  • Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

  • Prior Systemic Therapy Criteria:

    • Cohort A1/C1: Participant has received all standard therapies for which the participant was deemed to be an appropriate candidate by the treating Investigator; OR the participant is refusing the remaining most appropriate standard of care treatment; OR there is no standard therapy available for the disease. There is no restriction on number of prior therapies.
    • Cohort A2/B1/B2/B3: Participants must have received at least one prior regimen in the advanced or metastatic setting. There is no restriction on number of prior therapies.

  • FGFR inhibitor specific requirements:

    • Cohort A1/A2: Prior FGFR inhibitor treatment is permitted, but not required.
    • Cohort B1: Participants must have been previously treated with a FGFR inhibitor.
    • Cohort B2, B3, C1: Participants must be FGFR inhibitor naïve.

Exclusion Criteria:

  • Participants with primary central nervous system (CNS) malignancy.
  • Known or suspected history of uncontrolled CNS metastases.
  • Current evidence of corneal keratopathy or retinal disorder.
  • Have a history and/or current evidence of extensive tissue calcification.
  • Any serious unresolved toxicities from prior therapy.
  • Significant cardiovascular disease.
  • Prolongation of the QT interval corrected for heart rate using Fridericia's formula (QTcF).
  • Active uncontrolled systemic infection or other clinically significant medical conditions.
  • Participants who are pregnant, lactating, or plan to breastfeed during the study or within 6 months of the last dose of study treatment. Participants who have stopped breastfeeding may be enrolled.
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): NCT05614739


Contacts
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Contact: Patient Advocacy 855-569-6305 clinicaltrials@loxooncology.com

Locations
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Sponsors and Collaborators
Eli Lilly and Company
Loxo Oncology, Inc.
Merck Sharp & Dohme LLC
Investigators
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Study Director: Ryan Widau, PhD Loxo Oncology, Inc.
More Information
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Additional Information:

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Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT05614739    
Other Study ID Numbers: LOXO-FG3-22001
J4G-OX-JZVA ( Other Identifier: Eli Lilly and Company )
2022-502755-59-00 ( Other Identifier: EU CTR # )
KEYNOTE-F35 ( Other Identifier: Merck Sharp & Dohme, LLC )
MK-3475-F35 ( Other Identifier: Merck Sharp & Dohme, LLC )
First Posted: November 14, 2022    Key Record Dates
Last Update Posted: April 5, 2024
Last Verified: April 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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 Eli Lilly and Company:
Bladder Cancer
Bladder Urothelial Carcinoma
Urinary Bladder Cancer
 Urinary Tract Cancer
Renal Pelvis Cancer
Ureter Cancer
Additional relevant MeSH terms:
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Neoplasms
Neoplasm Metastasis
Urinary Bladder Neoplasms
Ureteral Neoplasms
Neoplastic Processes
Pathologic Processes
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Female Urogenital Diseases
Female Urogenital Diseases and Pregnancy Complications
 Urogenital Diseases
Urinary Bladder Diseases
Urologic Diseases
Male Urogenital Diseases
Ureteral Diseases
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action