FORAGER-1: A Study of Vepugratinib (LY3866288; LOXO-435) in Participants With Cancer With a Change in a Gene Called FGFR3

Purpose

The main purpose of this study is to learn more about the safety, side effects, and effectiveness of Vepugratinib by itself or when it is combined with other medicines that treat cancer. Vepugratinib 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). Study participation could last up to approximately 6 years, depending on which part of the study you join.

Conditions

  • Urinary Bladder Neoplasms
  • Neoplasm Metastasis
  • Ureteral Neoplasms

Eligibility

Eligible Ages
Over 18 Years
Eligible Sex
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  • Cohort A1, C1, D1, and D2: Locally advanced or metastatic solid tumor malignancy with a qualifying FGFR3 alteration. - Cohort A2, B2, B5 and B7: Urothelial cancer (UC) that is locally advanced or metastatic with a qualifying FGFR3 genetic alteration. - Cohorts B1 and B4: Urothelial cancer that is locally advanced or metastatic and have received prior erdafitinib. - Cohort B6: Muscle Invasive Bladder Cancer with a qualifying FGFR3 alteration. - Cohort B7: Urothelial cancer that is locally advanced or metastatic with a qualifying FGFR3 genetic alteration and expression of human epidermal growth factor receptor 2 (HER2). - Cohort B8: Low Grade Intermediate Risk Non-Muscle Invasive Bladder cancer and a qualifying FGFR3 genetic alteration. - Measurability of disease: - Cohort A1, D1, and D2: Measurable or non-measurable disease as defined by Response Evaluation Criteria in Solid Tumors v 1.1 (RECIST v1.1). - Cohorts A2, B1, B2, B4, B5, B7, and C1: Measurable disease required as defined by RECIST v1.1. - Cohort B8: Baseline disease which includes at least 1 lesion. - Have an Eastern Cooperative Oncology Group (ECOG) performance status of: - 0 or 1 for Cohorts A1, A2, B5, B6, B7, and B8. - Less than or equal to 2 for Cohorts B1, B2, B4, C1, DI and D2. - Cohort B6: Must be eligible for radical cystectomy plus pelvic lymph node dissection and agree to undergo curative intent standard radical cystectomy plus pelvic lymph node dissection.

Exclusion Criteria

  • Participants with primary central nervous system (CNS) malignancy. - Untreated or uncontrolled CNS metastases. - Current evidence of corneal keratopathy or retinal disorder. Individuals with asymptomatic ophthalmic conditions may be eligible. - 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. - Cohort D1 only: - Have had renal transplantation. - Have a known history of nephrotic syndrome. - Have uncontrolled fluid overload, including clinically significant ascites, pleural effusion, or peripheral edema. - Have uncontrolled hypertension. - Are on hemodialysis or similar. - Cohort D2 only: - Have a history of: - Ventricular tachycardia or ventricular fibrillation. - Hypertrophic obstructive cardiomyopathy unless managed concurrently with atrial fibrillation. - Wolff-Parkinson-White syndrome. - Second- or third-degree atrioventricular block unless a functioning pacemaker is in place. - Heart rate less than (<) 50 bpm. - Have any of these medical conditions: - Severe respiratory insufficiency. - Sleep apnea syndrome. - Myasthenia gravis. - Acute narrow-angle glaucoma. - Active liver disease or clinically significant hepatic impairment. - History of myopathy or rhabdomyolysis with any HMG-CoA reductase inhibitor.

Study Design

Phase
Phase 1
Study Type
Interventional
Allocation
Non-Randomized
Intervention Model
Sequential Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Phase 1a: Cohort A1 Vepugratinib Monotherapy Dose Escalation 		Vepugratinib administered orally
  • Drug: Vepugratinib
    Oral
    Other names:
    • LY3866288
    • LOXO-435
Experimental
Phase 1a: Cohort A2 Vepugratinib Monotherapy Dose Optimization 		Vepugratinib administered orally
  • Drug: Vepugratinib
    Oral
    Other names:
    • LY3866288
    • LOXO-435
Experimental
Phase 1b: Cohort B1, B2, B4, C1, and D1 Vepugratinib Monotherapy Dose Expansion 		Vepugratinib administered orally
  • Drug: Vepugratinib
    Oral
    Other names:
    • LY3866288
    • LOXO-435
Experimental
Phase 1b: Cohort B5 Vepugratinib Plus Pembrolizumab Plus Enfortumab Vedotin 		Vepugratinib administered orally in combination with pembrolizumab administered IV and enfortumab vedotin administered IV
  • Drug: Vepugratinib
    Oral
    Other names:
    • LY3866288
    • LOXO-435
  • Drug: Pembrolizumab
    IV
  • Drug: enfortumab vedotin
    IV
Experimental
Phase 1b: MIBC Cohort B6 Vepugratinib Plus Pembrolizumab Plus Enfortumab Vedotin 		Vepugratinib administered orally in combination with pembrolizumab administered IV and enfortumab vedotin administered IV
  • Drug: Vepugratinib
    Oral
    Other names:
    • LY3866288
    • LOXO-435
  • Drug: Pembrolizumab
    IV
  • Drug: enfortumab vedotin
    IV
Experimental
Experimental: Phase 1b: Cohort B7 Vepugratinib Plus Trastuzumab Deruxtecan 		Vepugratinib administered orally in combination with trastuzumab deruxtecan administered IV
  • Drug: Vepugratinib
    Oral
    Other names:
    • LY3866288
    • LOXO-435
  • Drug: Trastuzumab Deruxtecan
    IV
Experimental
Phase 1b: NMIBC Cohort B8 Vepugratinib Monotherapy Dose Expansion 		Vepugratinib administered orally
  • Drug: Vepugratinib
    Oral
    Other names:
    • LY3866288
    • LOXO-435
Experimental
Phase 1b: Cohort D2 (Drug to Drug Interaction) 		Vepugratinib Plus Midazolam Plus Digoxin Plus Rosuvastatin (Lead-In Only) followed by Vepugratinib Monotherapy Vepugratinib administered orally Midazolam with digoxin with rosuvastatin administered orally once per cycle for 2 cycles.
  • Drug: Vepugratinib
    Oral
    Other names:
    • LY3866288
    • LOXO-435
  • Drug: Midazolam
    Oral
  • Drug: Digoxin
    Oral
  • Drug: Rosuvastatin
    Oral

Recruiting Locations

Massachusetts General Hospital
Boston, Massachusetts 02114

More Details

Status
Recruiting
Sponsor
Eli Lilly and Company

Study Contact

Trial questions or participation questions: 1-877-CTLILLY (1-877-285-4559) or
1-317-615-4559
LillyTrials@Lilly.com

Detailed Description

This is an open-label, multi-center, phase 1 study in participants with FGFR3-altered advanced solid tumor malignancy including metastatic urothelial cancer (UC), muscle-invasive bladder cancer (MIBC), and low grade intermediate risk non-muscle-invasive bladder cancer (LG IR NMIBC). The study will be conducted in 2 phases. Phase 1a will assess safety, tolerability, and pharmacokinetics of Vepugratinib to determine the optimal dose for further expansion. Phase 1b will include dose expansion cohorts to evaluate the efficacy and safety of Vepugratinib as monotherapy or in combinations with other medicines that treat cancer.