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

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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An Open-Label, Multicenter Study of LOXO-435 (LY3866288) In Advanced Solid Tumor Malignancies With FGFR3 Alterations

Conditions
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Urinary Bladder Neoplasms, Neoplasm Metastasis, Ureteral Neoplasms

Intervention / Treatment
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* Drug: LOXO-435
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1a: Cohort A1 LOXO-435 Monotherapy Dose Escalation<br>LOXO-435 administered orally to participants with FGFR3-altered advanced solid tumors. | Drug: LOXO-435<br>* Oral<br>* Other names: LY3866288;|
| Experimental: Phase 1a: Cohort A2 LOXO-435 Monotherapy Dose Optimization<br>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<br>* Oral<br>* Other names: LY3866288;|
| Experimental: Phase 1b: Cohort B1 LOXO-435 Monotherapy Dose Expansion<br>LOXO-435 administered orally to participants with FGFR3-altered advanced urothelial carcinoma who were previously treated with an FGFR inhibitor. | Drug: LOXO-435<br>* Oral<br>* Other names: LY3866288;|
| Experimental: Phase 1b: Cohort B2 LOXO-435 Monotherapy Dose Expansion<br>LOXO-435 administered orally to participants with FGFR3-altered advanced urothelial carcinoma who have not received a prior FGFR inhibitor. | Drug: LOXO-435<br>* Oral<br>* Other names: LY3866288;|
| Experimental: Phase 1b: Cohort B3 LOXO-435 Plus Pembrolizumab<br>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<br>* Oral<br>* Other names: LY3866288;Drug: Pembrolizumab<br>* IV<br>|
| Experimental: Phase 1b: Cohort C1 LOXO-435 Monotherapy Dose Expansion<br>LOXO-435 administered orally to participants with advanced solid tumors who have not received a prior FGFR inhibitor. | Drug: LOXO-435<br>* Oral<br>* Other names: LY3866288;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1a: To determine the recommended phase 2 dose (RP2D)/optimal dose of LOXO-435: Safety, number of participants with dose-limiting toxicities (DLTs) | Number of participants with DLTs | Minimum of the first 21-day cycle of LOXO-435 treatment | 
| Phase 1b: To evaluate the preliminary antitumor activity of LOXO-435: Overall response rate (ORR) | ORR per investigator assessed RECIST v1.1 | Up to approximately 30 months or 2.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the pharmacokinetics (PK) of LOXO-435: Area under the concentration versus time curve (AUC) | PK of LOXO-435: AUC | Up to 2 months | 
| To assess the PK of LOXO-435: Minimum plasma concentration (Cmin) | PK of LOXO-435: Cmin | Up to 2 months | 
| To evaluate the preliminary antitumor activity of LOXO-435: Duration of response (DoR) | DOR per investigator assessed RECIST 1.1 | Up to approximately 30 months or 2.5 years | 
| To evaluate the preliminary antitumor activity of LOXO-435: Time to response (TTR) | TTR | Up to approximately 30 months or 2.5 years | 
| To evaluate the preliminary antitumor activity of LOXO-435: Progression-free survival (PFS) | PFS per investigator assessed RECIST 1.1 | Up to approximately 30 months or 2.5 years | 
| To evaluate the preliminary antitumor activity of LOXO-435: Disease control rate (DCR) | DCR per investigator assessed RECIST 1.1 | Up to approximately 30 months or 2.5 years | 
| To evaluate the preliminary antitumor activity of LOXO-435: Overall survival (OS) | OS | Up to approximately 30 months or 2.5 years | 
| Change from baseline in bladder-related symptoms, measured by Functional Assessment of Cancer Therapy - Bladder (FACT-Bl) subscale (BlCS) | 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 | Cycle 1 Day 1, Cycle 2 Day 1, and Cycle 3 Day 1 (28 day cycles) | 
| Change from baseline in physical function, measured by FACT- Physical Well-being Scale (PWB) subscale | 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. | Up to approximately 30 months or 2.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bladder Cancer, Bladder Urothelial Carcinoma, Urinary Bladder Cancer, Urinary Tract Cancer, Renal Pelvis Cancer, Ureter Cancer