Brief Title: BT8009-100 in Subjects With Nectin-4 Expressing Advanced Solid Tumors Malignancies

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Cohorts A-1, A-2 and C: Number of participants with treatment emergent adverse events receiving BT8009 alone and in combination with pembrolizumab to assess safety and tolerability

Primary Outcome 1 - Timeframe: 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)

Primary Outcome 2 - Measure: Cohorts A-1 and A-2 (escalations): Number of participants with dose limiting toxicities on BT8009 alone and in combination with pembrolizumab.

Primary Outcome 2 - Timeframe: 28 days (for cycles that are either 21 or 28 days in length depending on dosing schedule assigned).

Primary Outcome 3 - Measure: Cohorts B-1, B-2, and B-3 (expansions): Objective response rate (ORR) to assess the clinical activity of BT8009 as a monotherapy in patients with urothelial cancer using RECIST 1.1.

Primary Outcome 3 - Timeframe: Every 8 weeks for 12 months then every 12 weeks thereafter until disease progression or, death, or up to three years

Primary Outcome 4 - Measure: Cohorts B-4, B-5, and B-6 (expansions): Objective response rate (ORR) to assess the clinical activity of BT8009 as a monotherapy in patients with selected solid tumor indications associated with Nectin-4 expression using RECIST 1.1.

Primary Outcome 4 - Timeframe: Every 8 weeks for 12 months then every 12 weeks thereafter until disease progression or, death, or up to three years

Primary Outcome 5 - Measure: Cohort B-7 (expansion): Objective response rate (ORR) to assess the clinical activity of BT8009 in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma in combination with pembrolizumab using RECIST 1.1.

Primary Outcome 5 - Timeframe: Every 8 weeks for 12 months then every 12 weeks thereafter until disease progression or, death, or up to three years

CONDITION

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

ELIGIBILITY

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 recurred after or has been refractory to 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: 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 recurred after or has been refractory to prior therapy.

- Cohort B-5: Breast cancers that have been 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 recurred after or has been refractory to prior therapy.

- Cohort B-6: 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 recurred after or has been refractory to 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 that recurred after or has been refractory to prior therapy.
Key Exclusion Criteria (all patients):
Clinically relevant troponin elevation

- Uncontrolled diabetes

- Uncontrolled, symptomatic brain metastases

- 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

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: Meredith McKean, MD, MPH

Role: Study Chair

Affiliation: Tennessee Oncology, PLLC

Overall Contact

Name: Meredith McKean, MD, MPH

Phone: 617-945-8155

Email: clinicalstudies@bicycletx.com

LOCATION