A Study of Galunisertib (LY2157299) in Combination With Nivolumab in Advanced Refractory Solid Tumors and in Recurrent or Refractory NSCLC, or Hepatocellular Carcinoma

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate the safety, tolerability, and efficacy of the study drug known as galunisertib in combination with nivolumab in participants with advanced refractory solid tumors and in recurrent or refractory non-small cell lung cancer (NSCLC) or hepatocellular carcinoma (HCC).

Official Title
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A Phase 1b/2 Dose Escalation and Cohort Expansion Study of the Safety, Tolerability and Efficacy of a Novel Transforming Growth Factor-beta Receptor I Kinase Inhibitor (Galunisertib) Administered in Combination With Anti-PD-1 (Nivolumab) in Advanced Refractory Solid Tumors (Phase 1b) and in Recurrent or Refractory Non-small Cell Lung Cancer or Hepatocellular Carcinoma (Phase 2)

Conditions
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Solid Tumor, Non-Small Cell Lung Cancer Recurrent, Hepatocellular Carcinoma Recurrent

Intervention / Treatment
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* Drug: Galunisertib
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For Phase 1b, must have advanced refractory solid tumors in any line of therapy. For Phase 2, must have one of the following tumor types: recurrent or refractory NSCLC (any histology), or HCC with elevated alpha-fetoprotein (AFP) ≥200 nanogram/milliliter (ng/mL). For Phase 2 only, have had disease progression or be refractory or intolerant to 1 prior line of therapy (first line therapy) for recurrent or refractory for NSCLC or HCC and have refused currently approved second-line therapy. First line therapy is defined as therapy used to treat advanced disease. This may include multiple chemotherapeutic, targeted or immunotherapeutic agents with or without radiation therapy and/or surgery. Each subsequent line of therapy is preceded by disease progression. A switch of an agent within the same drug class (eg, cisplatinum to carboplatinum) within a regimen in order to manage toxicity does not define the start of a new line of therapy. For NSCLC: Prior lines of therapy must include a platinum-based therapy. Investigational agents used in combination with standard therapies are allowed. Participants who received platinum-based neoadjuvant or adjuvant therapy and subsequently received platinum-based therapy as first-line therapy are eligible. Participants who have completed neo-adjuvant or adjuvant therapy with a platinum doublet and have experienced disease recurrence within 6 months of completing the platinum doublet are eligible. Tumors with driver mutations (epidermal growth factor receptor mutation positive or anaplastic lymphoma kinase fusion oncogene positive) treated with a tyrosine kinase inhibitor or crizotinib are eligible. For participants who have progressed on a tyrosine kinase inhibitor or crizotinib or are intolerant to this targeted therapy, that participant must receive platinum-based therapy prior to enrollment in this study. Documentation of such mutations must be available and entered into the electronic case report form (eCRF). Maintenance or switch maintenance therapy after first-line chemotherapy will be considered part of the first-line regimen and is acceptable. Participants who completed and progressed on a platinum-containing regimen as adjuvant, neoadjuvant, or part of a course of chemoradiation therapy given from locally advanced disease and developed recurrent (local or metastatic) disease within the 6 months before screening would be counted as having received 1 prior platinum-containing regimen and therefore would not require re-treatment with a platinum-containing regimen for Stage IIIB, IV, or recurrent disease and are eligible. However, participants must have received at least 2 cycles of a platinum doublet based chemotherapy before discontinuation for toxicity. If participants received only one cycle of a platinum doublet and discontinue due to clear progression, that regimen should be counted as a prior line of therapy. For HCC: One prior line of therapy which must include sorafenib or participant must have progressed or been intolerant to sorafenib for participants not eligible for transarterial chemoembolization. Participants who had sorafenib for locally advanced disease or are intolerant to sorafenib are eligible. Participants may have had clinical progression only following sorafenib or local therapy. Must have Child-Pugh A only. Participants may have any viral status (hepatitis B, hepatitis C, or none). Have a viral load <100 international units/milliliter (IU/mL). For hepatitis B participants, must be on a nucleoside analog reverse transcriptase inhibitor (lamivudine, telbivudine, adefovir, tenofovir, or entecavir). Have adequate organ function. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale. Use an approved contraceptive method. Exclusion Criteria: For Phase 2 only, more than 1 prior line of therapy for their tumor type. Have moderate or severe cardiovascular disease: Have the presence of cardiac disease, including a myocardial infarction within 6 months prior to study entry, unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, or uncontrolled hypertension. Have documented major electrocardiogram (ECG) abnormalities which are clinically significant at the investigator's discretion (for example, symptomatic or sustained atrial or ventricular arrhythmias, second- or third-degree atrioventricular block, bundle-branch blocks, ventricular hypertrophy, or recent myocardial infarction). Have major abnormalities documented by ECHO with Doppler: Moderate or severe heart valve function defect including moderate or severe valve stenosis or regurgitation. Left ventricular (LV) ejection fraction <50%, evaluation based on the institutional lower limit of normal. Have septal aneurysm or other heart aneurysm. Any aneurysm of the major vessels. Active infection with hepatitis B virus (HBV) (positive hepatitis B surface antigen); HCV is allowed only in HCC participants. HCC participants at risk for HBV reactivation (as defined by anti-hepatitis B core antibody positive) are only eligible in the HCC cohort. Have evidence of interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity or active, noninfectious pneumonitis.

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: Galunisertib + Nivolumab (Cohort 1) Phase 1b<br>50 milligrams (mg) Galunisertib administered orally once daily (QD) on Day 1 through Day 14 of each 4-week cycle in combination with 3 milligrams per kilogram (3 mg/kg) nivolumab given intravenously (IV), every 2 weeks (Q2W), (Day 1 and Day 15). Participants may continue to receive study drug until discontinuation criteria are met. | Drug: Galunisertib<br>* Administered orally<br>* Other names: LY2157299;Drug: Nivolumab<br>* Administered IV<br>* Other names: OPDIVO®;|
| Experimental: Galunisertib + Nivolumab (Cohort 2) Phase 1b<br>50 mg Galunisertib administered orally twice daily (BID) on Day 1 through Day 14 of each 4-week cycle in combination with 3 mg/kg nivolumab given IV, Q2W,(Day 1 and Day 15). Participants may continue to receive study drug until discontinuation criteria are met. | Drug: Galunisertib<br>* Administered orally<br>* Other names: LY2157299;Drug: Nivolumab<br>* Administered IV<br>* Other names: OPDIVO®;|
| Experimental: Galunisertib + Nivolumab (Cohort 3) Phase 1b<br>80 mg Galunisertib administered orally BID on Day 1 through Day 14 of each 4-week cycle in combination with 3 mg/kg nivolumab given IV, Q2W, (Day 1 and Day 15). Participants may continue to receive study drug until discontinuation criteria are met. | Drug: Galunisertib<br>* Administered orally<br>* Other names: LY2157299;Drug: Nivolumab<br>* Administered IV<br>* Other names: OPDIVO®;|
| Experimental: Galunisertib + Nivolumab (Cohort 4) Phase 1b<br>150 mg Galunisertib administered orally BID on Day 1 through Day 14 of each 4-week cycle in combination with 3 mg/kg nivolumab given IV, Q2W,(Day 1 and Day 15). Participants may continue to receive study drug until discontinuation criteria are met. | Drug: Galunisertib<br>* Administered orally<br>* Other names: LY2157299;Drug: Nivolumab<br>* Administered IV<br>* Other names: OPDIVO®;|
| Experimental: Galunisertib + Nivolumab - Non-small Cell Lung Cancer (NSCLC) Phase 2<br>150 mg Galunisertib administered orally BID for the first 14 days of each 4-week cycle in combination with 3 mg/kg nivolumab given IV, Q2W, (Day 1 and Day 15) of each 4-week cycle. Participants may continue to receive study drug until discontinuation criteria are met. | Drug: Galunisertib<br>* Administered orally<br>* Other names: LY2157299;Drug: Nivolumab<br>* Administered IV<br>* Other names: OPDIVO®;|
| Experimental: Galunisertib + Nivolumab - Hepatocellular Carcinoma (HCC) Phase 2<br>150 mg Galunisertib administered orally BID for the first 14 days of each 4-week cycle in combination with 3 mg/kg nivolumab given IV, Q2W, (Day 1 and Day 15) of each 4-week cycle. Participants may continue to receive study drug until discontinuation criteria are met. | Drug: Galunisertib<br>* Administered orally<br>* Other names: LY2157299;Drug: Nivolumab<br>* Administered IV<br>* Other names: OPDIVO®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Maximum Tolerated Dose (MTD) of Galunisertib in Combination With Nivolumab | The MTD is defined as the highest tested dose that has less than 33% probability of causing a dose limiting toxicity (DLT). | Cycle 1 through Cycle 2 (Up to 2 Months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK): Minimum Concentration (Cmin) of Nivolumab | Minimum Concentration (Cmin) of Nivolumab | PK: Cycle 1 Day 15 Predose; Cycle 2: Day 1: Pre-dose; Day 15: Predose: Cycle 4: Day 1: Predose | 
| PK: Area Under the Plasma Concentration -Time Curve of Galunisertib From Time Zero to 24 Hours (AUC [0-24h]) at Steady State | Area under the plasma concentration curve from time zero to 24 hours of galunisertib for Cycle 1 and Cycle 2. | PK: Cycle 1 and Cycle 2 Day 1: Predose, 0.5 - 3 hours postdose, Cycle 1 and Cycle 2 Day 14: Predose, 0.5 - 2, 3.5 - 5, and 24 hours postdose through Cycle 4 Day 1 predose | 
| Number of Participants With Anti-Nivolumab Antibodies When Administered in Combination With Galunisertib | Participants with treatment-emergent anti-nivolumab antibodies when administered with galunisertib were participants with a 4-fold or greater increase in titer from baseline measurement (treatment-boosted). If baseline result is ADA not present, then the subject is TE ADA+, if there is at least 1 postbaseline result of ADA present with titer ≥ 40 (treatment-induced). | Cycle 1: Days 1, 14, 15 Predose and Day 100 Follow-up; Cycles 2 and 4: Day 1 Predose and Day 100 Follow-up | 
| Phase 2: Progression Free Survival (PFS) | PFS was defined as the time from the date of first study treatment to the first evidence of disease progression as defined by response evaluation criteria in solid tumors (RECIST) v1.1 or death from any cause. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. If a participant does not have a complete baseline disease assessment, then the PFS time was censored at the date of randomization, regardless of whether or not objectively determined disease progression or death has been observed for the participant. If a participant was not known to have died or have objective progression as of the data inclusion cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date. | Date of First Study Treatment to Measured Progressive Disease or Death (Up to 35 Months) | 
| Phase 2: Percentage of Participants Who Achieve Best Overall Tumor Response of Complete Response or Partial Response: Objective Response Rate (ORR) | Objective Response Rate was the percentage of participants achieving a best overall response (BOR) of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. PD was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. Overall response rate is calculated as a total number of participants with CR or PR divided by the total number of participants with at least 1 measurable lesion, multiplied by 100. | Baseline to Measured Progressive Disease (Up to 35 Months) | 
| Phase 2: Duration of Response (DoR) | Duration of response was measured from the date of documented response to the date of first progression of disease or the date of death due to any cause, whichever is earlier. | Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression or Death Due to Any Cause (Up to 35 Months) | 
| Phase 2: Time to Response | Time to response was measured from the date of first study treatment to the first documented response of Complete Response (CR) or Partial Response (PR). | Date of First Study Treatment to Date of Complete Response or Partial Response (Up to 35 Months) | 
| Phase 2: Overall Survival (OS) | Overall Survival was determined from the date of first study treatment until death due to any cause. | Date of First Study Treatment to Death from Any Cause (Up to 35 Months) |