A Study in Advanced Cancer

Participants may include those who have previously received treatment with another hedgehog smoothened (Hh/Smo) inhibitor (excluding LY2940680).

• Taladegib (Drug), also known as LY2940680: Administered IV

Primary outcomes

• Recommended Phase 2 Dose: Maximum Tolerated Dose [Time to First Dose to the End of Cycle 1 of Part A (Up To 28 Days)]: Recommended Phase 2 dose was determined by maximum tolerated dose (MTD), which was determined by Dose-limiting toxicity (DLT). For the purpose of this study, the MTD was defined as the highest tested dose that had <33% probability of causing a DLT in Cycle 1 of Part A.

Secondary outcomes

• Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC[0-∞]) [Cycle 1, Day 1: Predose, 0.5, 1, 2, 4, 6, 8, 10,11, 12 hour(h), Day 15: Predose, 0.5, 1, 2, 4, 6, 8, 10,11, 12 h]: Pharmacokinetics (PK): 1.Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC\[0-∞\])
• PK: Maximum Observed Drug Concentration (Cmax) [Cycle 1, Day 1: Predose, 0.5, 1, 2, 4, 6, 8, 10,11, 12 hour(h), Day 15: Predose, 0.5, 1, 2, 4, 6, 8, 10,11, 12 h]: PK: Maximum Observed Drug Concentration (Cmax)
• PK: Time of Maximal Concentration (Tmax) [Cycle 1, Day 1: Predose, 0.5, 1, 2, 4, 6, 8, 10,11, 12 hour(h), Day 15: Predose, 0.5, 1, 2, 4, 6, 8, 10,11, 12 h]: PK: Time of Maximal Concentration (Tmax)
• PK: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) of LSN3185556 [Cycle 1, Day 1: Predose, 0.5, 1, 2, 4, 6, 8, 10,11, 12 hour(h), Day 15: Predose, 0.5, 1, 2, 4, 6, 8, 10,11, 12 h]: PK: Area Under the Plasma Concentration-time Curve from time Zero to 24 Hours (AUC\[0-24\]) of LSN3185556
• PK: Maximum Observed Drug Concentration (Cmax) of LSN3185556 [Cycle 1, Day 1: Predose, 0.5, 1, 2, 4, 6, 8, 10,11, 12 hour(h), Day 15: Predose, 0.5, 1, 2, 4, 6, 8, 10,11, 12 h]: PK: Maximum Observed Drug Concentration (Cmax) of LSN3185556
• PK: Time of Maximal Concentration (Tmax) of LSN3185556 [Cycle 1, Day 1: Predose, 0.5, 1, 2, 4, 6, 8, 10,11, 12 hour(h), Day 15: Predose, 0.5, 1, 2, 4, 6, 8, 10,11, 12 h]: PK: Time of Maximal Concentration (Tmax)
• Number of Participants With Clinical Benefit Rate (Stable Disease [SD] + Partial Response [PR] + Complete Response [CR]) [Baseline to Disease Progression or Death Due to Any Cause (Up To 32 Months)]: Clinical Benefit Rate is complete response (CR) + partial response (PR) + stable disease (SD) as classified by the investigator according to the Response Evaluation Criteria In Solid Tumors (RECIST version 1.1) guidelines. CR is disappearance of all target and non-target lesions; PR is ≥30% decrease in sum of longest diameter of target lesions. SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD is a ≥20% increase in the sum of diameter of the target lesions taking as reference the smallest sum on study and an absolute increase in the sum diameter of ≥5 millimeter (mm), the appearance of 1 or more new lesions and/or unequivocal progression of existing nontarget lesions.
• Part C and D: Progression Free Survival (PFS) [Baseline to Progressive Disease or Death from Any Cause (Up To 32 Months)]: For each participant in Part C and D who is not known to have died or to have had a progression of disease as of the data inclusion cut-off date, PFS was censored at the date of last objective progression-free disease assessment prior to the date of any subsequent systemic anticancer therapy. Progressive disease (PD) was determined using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) criteria. PD is ≥20% increase in sum of longest diameter of target lesions and/or a new lesion.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Have histological or cytological evidence of a diagnosis of cancer that is advanced and/or metastatic. The patient must be, in the judgment of the investigator, an appropriate candidate for experimental therapy.
* Have the presence of measurable or nonmeasurable disease
* Have adequate organ function, including:

  * Hematologic: Absolute neutrophil count (ANC) greater than or equal to 1.5 x 109/L, platelets greater than or equal to 100 x 109/L, and hemoglobin greater than or equal to 9 g/dL. Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin until 5 days after the erythrocyte transfusion.
  * Hepatic: Bilirubin less than or equal to 1.5 times upper limits of normal (ULN), ALT, and aspartate transferase (AST) less than or equal to 2.0 times ULN. If the liver has tumor involvement AST and ALT equaling less than or equal to 5 times ULN are acceptable.
  * Renal: Serum creatinine less than or equal to 1.5 times ULN.
* Have a performance status of less than or equal to 1 on the Eastern Cooperative Oncology Group (ECOG) scale
* Have discontinued previous treatments for cancer and recovered from the acute effects of therapy (for example, at least 42 days for mitomycin-C or nitrosoureas, 28 days for other chemotherapy and biologics. At the discretion of the investigator, hormone refractory prostate cancer patients who are stable on gonadotropin-releasing hormone (GnRH) agonist therapy and breast cancer patients who are stable on antiestrogen therapy (for example, an aromatase inhibitor) may continue treatment

Exclusion Criteria:

* Have received treatment within 21 days of the initial dose of study drug with an experimental agent for noncancer indications that has not received regulatory approval for any indication.
* Have serious preexisting medical conditions
* Have symptomatic central nervous system (CNS) malignancy (with the exception of medulloblastoma) or metastasis (screening not required). Patients with treated CNS metastases are eligible for this study if they are not currently receiving corticosteroids and/or anticonvulsants, and their disease is asymptomatic and radiographically stable for at least 60 days.
* Have known current hematologic malignancies or acute or chronic leukemia
* Have a known active fungal, bacterial, and/or known viral infection including human immunodeficiency (HIV) or viral (A, B, or C) hepatitis (screening is not required)
* Have a second primary malignancy that in the judgment of the investigator and sponsor may affect the interpretation of results
* Have QTc interval of >500 msec on screening electrocardiogram
* Patients who have previously received treatment with LY2940680

Participant flow

Outcome results

• Recommended Phase 2 Dose: Maximum Tolerated Dose (Primary), Number, milligrams (mg): All Part A Participants 400
• Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC[0-∞]) (Secondary), Geometric mean, nanogram*hour/milliliter (μg*h/mL): 50 mg Taladegib NA +/- NA; 100 mg Taladegib 8.70 +/- 101; 200 mg Taladegib NA +/- NA; 400 mg Taladegib 53.7 +/- 99.1; 600 mg Taladegib 96.2 +/- 74.8
• PK: Maximum Observed Drug Concentration (Cmax) (Secondary), Geometric mean, microgram per milliliter (μg/mL): 50 mg Taladegib NA +/- NA; 100 mg Taladegib 0.45 +/- 59.87; 200 mg Taladegib 1.29 +/- NA; 400 mg Taladegib 2.07 +/- 66.39; 600 mg Taladegib 3.28 +/- 34.36
• PK: Time of Maximal Concentration (Tmax) (Secondary), Median, hour (h): 50 mg Taladegib 2.03 (2.00 to 2.22); 100 mg Taladegib 3.92 (2.00 to 4.00); 200 mg Taladegib 1.22 (0.75 to 4.00); 400 mg Taladegib 2.00 (0.02 to 24.17); 600 mg Taladegib 3.82 (1 to 6)
• PK: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) of LSN3185556 (Secondary), Geometric mean, microgram*hour/milliliter (μg*h/mL): 50 mg Taladegib NA +/- NA; 100 mg Taladegib 7.91 +/- 50.1; 200 mg Taladegib NA +/- NA; 400 mg Taladegib 36.6 +/- 70.1; 600 mg Taladegib 67.4 +/- 67.7
• PK: Maximum Observed Drug Concentration (Cmax) of LSN3185556 (Secondary), Geometric mean, microgram per milliliter (μg/mL): 50 mg Taladegib NA +/- NA; 100 mg Taladegib 0.51 +/- 37.28; 200 mg Taladegib NA +/- NA; 400 mg Taladegib 2.27 +/- 62.82; 600 mg Taladegib 4.18 +/- 73.72
• PK: Time of Maximal Concentration (Tmax) of LSN3185556 (Secondary), Median, hour (h): 50 mg Taladegib 24.25 (8.00 to 24.48); 100 mg Taladegib 16.81 (6.12 to 24.43); 200 mg Taladegib 6.00 (2.00 to 24.08); 400 mg Taladegib 22.67 (1.13 to 25.17); 600 mg Taladegib 24.00 (7.98 to 24.87)
• Number of Participants With Clinical Benefit Rate (Stable Disease [SD] + Partial Response [PR] + Complete Response [CR]) (Secondary), Count of participants, Participants: Part A: Cohort 1 2; Part A: Cohort 2 1; Part A: Cohort 3 2; Part A: Cohort 4 1; Part A: Cohort 5 2; Part C 4; Part D 37
• Part C and D: Progression Free Survival (PFS) (Secondary), Median, months: Part C 1.74 (0.95 to 1.87); Part D 9.07 (7.36 to NA)

Adverse events

Serious adverse events by term

Other adverse events by term

94 more terms not shown.

Limitations and caveats: Part B of the study was not implemented as the estimated half-life was considered long enough for QD dosing.

• Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Study director, Eli Lilly and Company