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

• 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

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	75 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group 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
Estimated Study Completion Date :	December 20, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Galunisertib + Nivolumab (Phase 1b); Galunisertib in escalating dose cohorts given orally daily or twice a day (BID) for the first 14 days of each 4 week cycle in combination with nivolumab given intravenously (IV) every 2 weeks for 2 cycles.	Drug: Galunisertib; Administered orally; Other Name: LY2157299; Drug: Nivolumab; Administered IV
Experimental: Galunisertib + Nivolumab (NSCLC) (Phase 2); Galunisertib given orally BID for the first 14 days of each 4 week cycle in combination with nivolumab given IV every 2 weeks 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
Experimental: Galunisertib + Nivolumab (HCC) (Phase 2); Galunisertib given orally BID for the first 14 days of each 4 week cycle in combination with nivolumab given IV every 2 weeks 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

Outcome Measures

Primary Outcome Measures :

1. Phase 1b: Maximum Tolerated Dose of Galunisertib in Combination with Nivolumab [ Time Frame: Cycle 1 through Cycle 2 (Estimated up to 2 Months) ]

Secondary Outcome Measures :

1. Pharmacokinetics (PK): Minimum Concentration (Cmin) of Nivolumab [ Time Frame: Cycle 1 Day 1 through Cycle 4 Day 1 (Estimated up to 4 Months) ]
2. PK: Steady State Concentration of Galunisertib [ Time Frame: Cycle 1 Day 1 through Cycle 4 Day 1 (Estimated up to 4 Months) ]
3. Number of Participants with Anti-Nivolumab Antibodies When Administered in Combination with Galunisertib [ Time Frame: Cycle 1 Day 1 through Follow-up (Estimated up to 6 Months) ]
4. Phase 2: Progression Free Survival (PFS) [ Time Frame: Baseline to Measured Progressive Disease or Death (Estimated up to 18 Months) ]
5. Phase 2: Number 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 (Estimated up to 18 Months) ]
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 (Estimated up to 18 Months) ]
7. Phase 2: Time to Response [ Time Frame: Baseline to Date of Complete Response (CR) or Partial Response (Estimated up to 4 Months) ]
8. Phase 2: Overall Survival (OS) [ Time Frame: Baseline to Death from Any Cause (Estimated up to 30 Months) ]

Eligibility Criteria

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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

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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

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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

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. 

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Responsible Party:	Eli Lilly and Company
ClinicalTrials.gov Identifier:	NCT02423343 History of Changes
Other Study ID Numbers:	15702; H9H-MC-JBEF ( Other Identifier: Eli Lilly and Company )
First Posted:	April 22, 2015
Last Update Posted:	February 15, 2019
Last Verified:	February 1, 2019

Additional relevant MeSH terms:

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Carcinoma; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Hepatocellular; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; 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