Study BT8009-100 in Subjects With Nectin-4 Expressing Advanced Malignancies

Phase I/II Study of the Safety, Pharmacokinetics, and Preliminary Clinical Activity of BT8009 in Patients With Nectin-4 Expressing Advanced Malignancies

This study is a Phase I/II, multicenter, first-in-human, open-label dose-escalation study of BT8009 given as a single agent and in combination with pembrolizumab in participants with advanced solid tumors associated with Nectin-4 expression or in participants with advanced solid tumor malignancies having renal insufficiency. The primary endpoints are Dose limiting toxicities (Parts A-1 and A-2), Overall response rate per RECIST v1.1 (Part B) and Safety and tolerability (Part C).

This study will assess the safety and tolerability of BT8009 alone and in combination with pembrolizumab in patients with select advanced solid tumors. BT8009 will be given as a single agent in 3 different dosing schedules- weekly (28 day cycle), biweekly (28 day cycle), or dosing on day 1 and day 8 of a 3-weekly (21 day cycle) and in combination with pembrolizumab. There are three parts to this study. Part A is a dose escalation in patients with select advanced solid tumors primarily designed to evaluate safety and tolerability of BT8009 as monotherapy or in combination with pembrolizumab and to determine a recommended Phase II dose (RP2D). Following a selection of an RP2D, Part B, a dose expansion portion, will be initiated with the primary objective of clinical activity of BT8009 as a monotherapy or in combination with pembrolizumab in patients with select advanced solid tumors. Part C will evaluate safety and tolerability of RP2D in patients with renal insufficiency.

Advanced Solid Tumor, Urinary Bladder Neoplasm, Triple Negative Breast Neoplasms, Carcinoma, Non-Small-Cell Lung, Ovarian Neoplasm

Bicyclic Toxin Conjugate (BTC) administered either weekly (i.e., on Days 1, 8, 15, and 22) or biweekly (Days 1 and 15) on a 28-day cycle or on Days 1 and 8 of a 21-day cycle for participants in A-1. Participants in Cohorts A-2 and B-7 will receive a 60-minute IV infusion of BT8009 on Days 1,8 and 15 of a 21-day cycle. Participants in Part B will receive BT8009 once weekly either on a 21-day or 28-day cycle. Participants in Cohort C will receive a 60-minute IV infusion of BT8009 once weekly (i.e., on Days 1, 8, 15, and 22) on a 28-day cycle.

Participants in Cohorts A-2 and B-7 will receive 200 mg IV over 30-minute infusion of pembrolizumab on Day 1 of each Q3W.

Parts A-1, A-2 and C: Number of participants with treatment emergent adverse events, receiving BT8009 as a monotherapy or in combination with pembrolizumab to assess safety and tolerability.

Parts A-1 and A-2 (escalations): Number of participants with dose limiting toxicities on BT8009 as a monotherapy or in combination with pembrolizumab

Number of patients who experience dose limiting toxicities BT8009 when given as a monotherapy or in combination with pembrolizumab.

Part B (all Cohorts): Objective response rate (ORR) to assess the clinical activity of BT8009 as a monotherapy or in combination with pembrolizumab using RECIST 1.1.

Proportion of participants with confirmed complete response or partial response to BT8009 as a monotherapy or in combination with pembrolizumab according to RECIST 1.1 criteria.

Every 8 weeks for 12 months then every 12 weeks thereafter until disease progression or, death, or up to three years

Part B: Number of participants with treatment emergent adverse events receiving BT8009 as a monotherapy or in combination with pembrolizumab to assess safety and tolerability.

Number of participants with advanced solid tumor malignancies associated with Nectin-4 expression receiving BT8009 as a monotherapy or in combination with pembrolizumab who experience treatment-emergent adverse events using CTCAE v5.0 criteria.

From cycle 1 day 1 until at least 30 days after the end of treatment (each cycle is 21 or 28 days depending on the assigned dosing schedule)

Part B: Duration of Response time to assess preliminary anti-tumor activity of BT8009 as a monotherapy or in combination with pembrolizumab

Duration of objective response (complete or partial response) by RECIST 1.1 in participants receiving BT8009 as a monotherapy or in combination with pembrolizumab

Every 8 weeks for 12 months then every 12 weeks thereafter until disease progression or, death, or up to three years

Part B: Clinical benefit rate to assess the clinical activity of BT8009 as a monotherapy or in combination with pembrolizumab

Proportion of participants who have complete response (CR), partial response (PR), or stable disease (SD) for at least 16 weeks according to RECIST Version 1.1 criteria.

Every 8 weeks for 12 months then every 12 weeks thereafter until disease progression or death or up to 3 years

Part B: Progression-free survival time to assess the clinical activity of BT8009 as a monotherapy or in combination with pembrolizumab.

The time from the first day of study drug administration (Day 1) to disease progression according to RECIST 1.1 criteria in participants receiving BT8009 as a monotherapy or in combination with pembrolizumab.

Every 8 weeks for the first 12 months then every 12 weeks until disease progression or death for up to three years

Part B: Overall survival time to assess the clinical activity of BT8009 as a monotherapy or in combination with pembrolizumab using RECIST 1.1

The time from start of study drug administration (Day 1) until death due to any cause in participants receiving BT8009 as a monotherapy or in combination with pembrolizumab.

Every 8 weeks for the first 12 months then every 12 weeks until death, then every 3 months for up to 1 year after last patient accrued

Cohorts B-4, B-5, and B-6: Objective response rate by Nectin-4 status of BT8009 as a monotherapy in patients with selected solid tumor using RECIST 1.1.

Proportion of participants with confirmed complete response or partial response to BT8009 as a monotherapy according to RECIST 1.1 criteria categorized by Nectin-4 expression status.

Every 8 weeks for the first 12 months then every 12 weeks until disease progression or death for up to three years

Parts A-1, A-2 and C: Objective response rate to assess preliminary anti-tumor activity of BT8009 as a monotherapy or in combination with pembrolizumab.

Proportion of participants with advanced solid tumor malignancies associated with Nectin-4 expression or advanced solid tumor malignancies having renal insufficiency with confirmed complete response or partial response according to RECIST 1.1 criteria

Every 8 weeks for the first 12 months then every 12 weeks until disease progression or death or up to three years

Parts A-1, A-2 and C: Duration of Response time to assess preliminary anti-tumor activity of BT8009 as a monotherapy or in combination with pembrolizumab.

Duration of objective response (complete or partial response) by RECIST 1.1 in participants with advanced solid tumor malignancies associated with Nectin-4 expression or advanced solid tumor malignancies having renal insufficiency receiving BT8009 as a monotherapy or in combination with pembrolizumab.

Every 8 weeks for the first 12 months then every 12 weeks until disease progression or death or up to three years

Parts A-1, A-2 and C: Clinical benefit rate to assess preliminary anti-tumor activity of BT8009 as a monotherapy or in combination with pembrolizumab.

Proportion of participants with advanced solid tumor malignancies associated with Nectin-4 expression or advanced solid tumor malignancies having renal insufficiency who have complete response (CR), partial response (PR) or stable disease (SD) for at least 16 weeks according to the RECIST Version 1.1 criteria.

Every 8 weeks for the first 12 months then every 12 weeks until disease progression for up to 3 years

Parts A-1, A-2 and C: Progression-free survival time (months) to assess preliminary anti-tumor activity of BT8009 as a monotherapy or in combination with pembrolizumab.

The time from start of study drug administration until disease progression according to RECIST 1.1 in participants with advanced solid tumor malignancies associated with Nectin-4 expression or advanced solid tumor malignancies having renal insufficiency receiving BT8009 as a monotherapy or in combination with pembrolizumab.

Every 8 weeks for the first 12 months then every 12 weeks until disease progression or death for up to three years

Parts A-1, A-2 and C: Overall survival time (months) to assess preliminary anti-tumor activity of BT8009 as a monotherapy or in combination with pembrolizumab.

The time from start of study drug administration until death due to any cause in participants with advanced solid tumor malignancies associated with Nectin-4 expression or advanced solid tumor malignancies having renal insufficiency receiving BT8009 as a monotherapy or in combination with pembrolizumab.

Every 8 weeks for the first 12 months then every 12 weeks until disease progression, then every 3 months for up to 1 year after last patient is accrued

All Parts: Maximum plasma concentration (Cmax) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherapy and in combination with pembrolizumab.

Plasma concentrations of BT8009 and MMAE from all participants taking BT8009 alone and in combination with pembrolizumab.

From Cycle 1 Day 1 through end of treatment or for up to 1 year (Cycles are 21 days or 28 days depending on the assigned dosing schedule)

All Parts: Minimum plasma concentration (Cmin) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherapy and in combination with pembrolizumab.

Plasma concentrations of BT8009 and MMAE from all participants taking BT8009 alone and in combination with pembrolizumab.

From Cycle 1 Day 1 through end of treatment or for up to 1 year (Cycles are 21 days or 28 days depending on the assigned dosing schedule)

All Parts: Area under the plasma concentration-time curve (AUC) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherapy and in combination with pembrolizumab.

Plasma concentrations of BT8009 and MMAE from all participants taking BT8009 alone and in combination with pembrolizumab.

From Cycle 1 Day 1 through end of treatment or for up to 1 year (Cycles are 21 days or 28 days depending on the assigned dosing schedule)

All Parts: Elimination half-life (t1/2) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherapy and in combination with pembrolizumab.

Plasma concentrations of BT8009 and MMAE from all participants taking BT8009 alone and in combination with pembrolizumab.

From Cycle 1 Day 1 through end of treatment or for up to 1 year (Cycles are 21 days or 28 days depending on the assigned dosing schedule)

Part C: Maximum plasma concentration (Cmax) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherapy.

Plasma concentrations (for impact of renal impairment) of BT8009 and MMAE from Part C participants taking BT8009 as a monotherapy.

From Cycle 1 Day 1 through end of treatment or for up to 1 year (Cycles are 21 days or 28 days depending on the assigned dosing schedule)

Part C: Minimum plasma concentration (Cmin) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherap.

Plasma concentrations (for impact of renal impairment) of BT8009 and MMAE from Part C participants taking BT8009 as a monotherapy.

From Cycle 1 Day 1 through end of treatment or for up to 1 year (Cycles are 21 days or 28 days depending on the assigned dosing schedule)

Part C: Area under the plasma concentration-time curve (AUC) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherapy.

Plasma concentrations (for impact of renal impairment) of BT8009 and MMAE from Part C participants taking BT8009 as a monotherapy.

From Cycle 1 Day 1 through end of treatment or for up to 1 year (Cycles are 21 days or 28 days depending on the assigned dosing schedule)

Part C: Elimination half-life (t1/2) of BT8009 and monomethyl auristatin E (MMAE) when given as monotherapy.

Plasma concentrations (for impact of renal impairment) of BT8009 and MMAE from Part C participants taking BT8009 as a monotherapy.

From Cycle 1 Day 1 through end of treatment or for up to 1 year (Cycles are 21 days or 28 days depending on the assigned dosing schedule)

All cohorts: Number of participants positive for anti-drug antibodies (ADA) to determine incidence of ADA

Number of participants positive for anti-drug antibodies (ADA) from all participants receiving BT8009 as a monotherapy or in combination with pembrolizumab

From Cycle 1 Day 1 through end of treatment or for up to 1 year (Cycles are 21 days or 28 days depending on the assigned dosing schedule)

Key Inclusion Criteria Life expectancy ≥12 weeks. Patients must have measurable disease per RECIST 1.1. Part A-1 cohorts: Must have exhausted all standard treatment options, including appropriate targeted therapies; or patients for which no standard therapy is considered appropriate Patients with advanced, histologically confirmed urothelial (transitional cell) carcinoma that recurred after or has been refractory to prior therapy (fresh tumor biopsy or an archived sample must be submitted); or Patients with advanced, histologically confirmed pancreatic, breast, non-small-cell lung cancer (NSCLC), gastric, esophageal, head and neck, or ovarian tumors that recurred after or has been refractory to prior therapy (fresh tumor biopsy or an archived sample testing for Nectin-4 expression). Part A-2: Must have exhausted all standard treatment options, including appropriate targeted therapies; or patients for which no standard therapy is considered appropriate Patients with advanced, histologically confirmed urothelial (transitional cell) carcinoma that have progressed following prior therapy Cohort B-1: Histologically documented urothelial carcinoma, previously treated with enfortumab vedotin (EV). Patients with resectable, locally advanced urothelial carcinoma are ineligible. Must have had progression or recurrence of urothelial cancer during or following receipt of most recent therapy. Cohort B-2 and B-3: Histologically documented urothelial carcinoma, not previously treated with enfortumab vedotin (EV). Patients with resectable, locally advanced urothelial carcinoma are ineligible. Must have had progression or recurrence of urothelial cancer during or following receipt of most recent therapy. Cohort B-4: Patients with histologically confirmed non-mucinous epithelial ovarian, fallopian tube, or primary peritoneal cancer that is Stage III or IV according to the International Federation of Gynecology and Obstetrics (FIGO) or tumor, node and metastasis staging criteria that have progressed following prior therapy. Cohort B-5: Patients with triple-negative breast cancer confirmed negative for estrogen receptor (ER) and progesterone receptor (PR) and negative for human epidermal growth factor receptor 2 (HER2) (i.e., triple-negative) that have progressed following prior therapy. Cohort B-6: Patients with histologically confirmed non-small cell lung cancer (NSCLC) with no actionable mutations, such as Epidermal Growth Factor Receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) fusion oncogene, or ROS1 that have progressed following prior therapy. Cohort B-7: Locally advanced or metastatic, histologically confirmed urothelial (transitional cell) carcinoma, ineligible for cisplatin, no prior systemic anticancer treatment for advanced urothelial carcinoma. Cohort C renal insufficiency cohort: Patients with histologically documented urothelial carcinoma, ovarian, triple negative breast, or non-small cell lung cancer that have been previously treated with a locally approved therapy. Key Exclusion Criteria (all patients): Clinically relevant troponin elevation Uncontrolled diabetes Known active or untreated CNS and/or carcinomatous meningitis Grade ≥2 peripheral neuropathy Active keratitis or corneal ulcerations Patients with uncontrolled hypertension History of another malignancy within 3 years before first dose of BT8009 or residual disease from a previously diagnosed malignancy (with some exceptions). Active systemic infection requiring therapy, or fever within the last 14 days prior to first dose of BT8009. Prior Stevens-Johnson syndrome/toxic epidermal necrolysis on any MMAE-conjugated drug Parts A-2 and B-7 Pembrolizumab Combination Cohorts: Prior organ transplant (including allogeneic) Diagnosis of clinically relevant immunodeficiency History of interstitial lung disease Parts B-2 and B-3: Prior treatment with enfortumab vedotin Other protocol-defined Inclusion/Exclusion criteria may apply