| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Advanced Refractory Solid
Tumours (Phase 1b) and in Recurrent or Refractory
Non–Small Cell Lung Cancer or Hepatocellular Carcinoma,
(Phase 2) |
|
| E.1.1.1 | Medical condition in easily understood language |
Advanced Refractory Solid
Tumours (Phase 1b) and in Recurrent or Refractory
Non–Small Cell Lung Cancer or Hepatocellular Carcinoma,
(Phase 2) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1b
The primary objective of the Phase 1b part of this study is to assess the safety and tolerability of
orally dosed galunisertib 14 days on/14 days off in combination with IV nivolumab 3 mg/kg
Q2W by identifying dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) or
pharmacologically active dose (PAD) of the combination in patients with advanced refractory
solid tumours during the first 2 cycles.
Phase 2
The primary objective of the Phase 2 part (expansion cohorts) of this study is to assess the safety of the combination of galunisertib and nivolumab in patients with refractory or recurrent NSCLC or HCC who have failed 1 prior line of therapy. |
|
| E.2.2 | Secondary objectives of the trial |
to characterize the PK of galunisertib and nivolumab when coadministered
to characterize the immunogenicity of nivolumab when administered in combination with galunisertib to estimate the OS rate following the final analysis/evaluation of OS and the landmark OS at 6, 12, and 18 months following the start of therapy with the combination of galunisertib and nivolumab
Phase 2 only: To assess the preliminary antitumour activity including PFS, ORR,
duration of response, and time to response of the combination of galunisertib and nivolumab in patients with NSCLC or HCC |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• For Phase 1b, must have advanced refractory solid tumors in any line of therapy. In the Phase 2 if fewer than 3 NSCLC, HCC or glioblastoma participants are not included in the Phase 1b, then a safety run-in must occur for any of the cohorts that have fewer than 3 participants in Phase 1.
• 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:
o 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.
o 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.
o 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).
o 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:
o 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.
o Must have Child-Pugh A only. Participants may have any viral status (hepatitis B, hepatitis C, or none).
o Have a viral load <100 international units/milliliter (IU/mL).
o 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.
|
|
| E.4 | Principal exclusion criteria |
• Have moderate or severe cardiovascular disease:
o 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.
o 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).
o Have major abnormalities documented by Echocardiogram with Doppler (for example, moderate or severe heart valve function defect and/or left ventricular ejection fraction <50%, evaluation based on the institutional lower limit of normal).
o Have predisposing conditions that are consistent with development of aneurysms of the ascending aorta or aortic stress (for example, personal history of aneurysm in any location, family history of aneurysms in any location, Marfan-Syndrome, bicuspid aortic valve, evidence of damage to the large vessels of the heart documented by computed tomography [CT] scan/magnetic resonance imaging [MRI] with contrast).
• 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.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Maximum Tolerated Dose of Galunisertib in Combination with Nivolumab |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Cycle 1 through Cycle 2 (Estimated up to 2 Months) |
|
| E.5.2 | Secondary end point(s) |
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Nivolumab
PK: Steady State Concentration of Galunisertib
Number of Participants with Anti-Nivolumab Antibodies When Administered in Combination with Galunisertib
Phase 2: Progression Free Survival (PFS)
Phase 2: Number of Participants who Achieve Best Overall Tumor Response of Complete Response or Partial Response: Objective Response Rate (ORR)
Phase 2: Duration of Response (DoR)
Phase 2: Time to Response
Phase 2: Overall Survival (OS)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Cmin of Nivolumab: Cycle 1 Day 1 through Cycle 4 Day 1 (Estimated up to 4 Months)
Steady State Concentration of Galunisertib: Cycle 1 Day 1 through Cycle 4 Day 1 (Estimated up to 4 Months)
Number of Participants with Anti-Nivolumab Antibodies: Cycle 1 Day 1 through Follow-up (Estimated up to 6 Months)
PFS: Baseline to Measured Progressive Disease or Death (Estimated up to 18 Months)
ORR: Baseline to Measured Progressive Disease (Estimated up to 18 Months)
DoR: Date of Complete Response or Partial Response to Date of Objective Disease Progression or Death Due to Any Cause (Estimated up to 18 Months)
Time to Response:Baseline to Date of Complete Response or Partial Response (Estimated up to 4 Months)
OS: Baseline to Death from Any Cause (Estimated up to 30 Months) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Dose escalation and dose expansion |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Germany |
| Spain |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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