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

• ClinicalTrials.gov Identifier: NCT02423343
• Recruitment Status: Completed
• First Posted: April 22, 2015
• Results First Posted: September 9, 2021
• Last Update Posted: September 9, 2021
• Sponsor: Eli Lilly and Company
• Collaborator: Bristol-Myers Squibb
• Information provided by (Responsible Party): Eli Lilly and Company

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Solid Tumor; Non-Small Cell Lung Cancer Recurrent; Hepatocellular Carcinoma Recurrent	Drug: Galunisertib; Drug: Nivolumab	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 41 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: January 1, 2015
• Actual Primary Completion Date: December 13, 2018
• Actual Study Completion Date: July 8, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Galunisertib + Nivolumab (Cohort 1) Phase 1b; 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; Administered orally; Other Name: LY2157299; Drug: Nivolumab; Administered IV; Other Name: OPDIVO®
Experimental: Galunisertib + Nivolumab (Cohort 2) Phase 1b; 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; Administered orally; Other Name: LY2157299; Drug: Nivolumab; Administered IV; Other Name: OPDIVO®
Experimental: Galunisertib + Nivolumab (Cohort 3) Phase 1b; 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; Administered orally; Other Name: LY2157299; Drug: Nivolumab; Administered IV; Other Name: OPDIVO®
Experimental: Galunisertib + Nivolumab (Cohort 4) Phase 1b; 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; Administered orally; Other Name: LY2157299; Drug: Nivolumab; Administered IV; Other Name: OPDIVO®
Experimental: Galunisertib + Nivolumab - Non-small Cell Lung Cancer (NSCLC) Phase 2; 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; Administered orally; Other Name: LY2157299; Drug: Nivolumab; Administered IV; Other Name: OPDIVO®
Experimental: Galunisertib + Nivolumab - Hepatocellular Carcinoma (HCC) Phase 2; 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; Administered orally; Other Name: LY2157299; Drug: Nivolumab; Administered IV; Other Name: OPDIVO®

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Pharmacokinetics (PK): Minimum Concentration (Cmin) of Nivolumab [ Time Frame: PK: Cycle 1 Day 15 Predose; Cycle 2: Day 1: Pre-dose; Day 15: Predose: Cycle 4: Day 1: Predose ]
   Minimum Concentration (Cmin) of Nivolumab
2. PK: Area Under the Plasma Concentration -Time Curve of Galunisertib From Time Zero to 24 Hours (AUC [0-24h]) at Steady State [ Time Frame: 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 ]
   Area under the plasma concentration curve from time zero to 24 hours of galunisertib for Cycle 1 and Cycle 2.
3. Number of Participants With Anti-Nivolumab Antibodies When Administered in Combination With Galunisertib [ Time Frame: Cycle 1: Days 1, 14, 15 Predose and Day 100 Follow-up; Cycles 2 and 4: Day 1 Predose and Day 100 Follow-up ]
   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).
4. Phase 2: Progression Free Survival (PFS) [ Time Frame: Date of First Study Treatment to Measured Progressive Disease or Death (Up to 35 Months) ]
   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.
5. Phase 2: Percentage of Participants Who Achieve Best Overall Tumor Response of Complete Response or Partial Response: Objective Response Rate (ORR) [ Time Frame: Baseline to Measured Progressive Disease (Up to 35 Months) ]
   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.
6. Phase 2: Duration of Response (DoR) [ Time Frame: 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) ]
   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.
7. Phase 2: Time to Response [ Time Frame: Date of First Study Treatment to Date of Complete Response or Partial Response (Up to 35 Months) ]
   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).
8. Phase 2: Overall Survival (OS) [ Time Frame: Date of First Study Treatment to Death from Any Cause (Up to 35 Months) ]
   Overall Survival was determined from the date of first study treatment until death due to any cause.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham Medical Center

Birmingham, Alabama, United States, 35294

United States, California

University of California - San Diego

La Jolla, California, United States, 92093

United States, Florida

H Lee Moffitt Cancer Center

Tampa, Florida, United States, 33612-9497

United States, Massachusetts

Dana Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, Texas

University of Texas MD Anderson Cancer Center

Houston, Texas, United States, 77030

Spain

Hospital Universitari Vall d'Hebron

Barcelona, Spain, 08035

Institut Catala d'Oncologia

Barcelona, Spain, 08907

Hospital Universitario 12 de Octubre

Madrid, Spain, 28041

Hospital Regional Universitario de Málaga

Malaga, Spain, 29010

Sponsors and Collaborators

Eli Lilly and Company

Bristol-Myers Squibb

Investigators

• Study Director: 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); Eli Lilly and Company

  Study Documents (Full-Text)

Documents provided by Eli Lilly and Company:

Study Protocol  [PDF] January 31, 2017

Statistical Analysis Plan  [PDF] October 26, 2017

More Information

Additional Information:

Description: Click here for more information about this study: A Study of Galunisertib (LY2157299) in Combination With Nivolumab in Advanced Refractory Solid Tumors and in Recurrent or Refractory NSCLC, or Hepatocellular Carcinoma. 

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT02423343
• Other Study ID Numbers: 15702; H9H-MC-JBEF ( Other Identifier: Eli Lilly and Company ); 2015-002093-20 ( EudraCT Number )
• First Posted: April 22, 2015
• Results First Posted: September 9, 2021
• Last Update Posted: September 9, 2021
• Last Verified: August 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)
• Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.
• Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• URL: http://vivli.org/

Additional relevant MeSH terms:

Carcinoma; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Hepatocellular; Recurrence; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Pathologic Processes; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Adenocarcinoma; Liver Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Nivolumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action