| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| hepatocellular carcinoma or liver cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10073071 |
| E.1.2 | Term | Hepatocellular carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
1-Phase Ib part:
To characterize the safety and tolerability of INC280 in combination with PDR001 and identify the MTD and/or RP2D
2-Phase II part:
To compare the efficacy of INC280 in combination with PDR001 vs.
PDR001 single agent |
|
| E.2.2 | Secondary objectives of the trial |
2-To characterize the safety and tolerability of INC280 combined with PDR001 and PDR001 single agent in the phase II part
1-To further characterize the efficacy of INC280 in combination with PDR001 and PDR001 single agent
3-To characterize the pharmacokinetic profile of INC280 combined with PDR001 and PDR001 single agent
4-To assess the pharmacodynamic effect of INC280 in combination with PDR001 and PDR001 single agent in tumor biopsy |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically or cytologically documented locally advanced recurrent or metastatic HCC or for patients with cirrhosis clinical diagnosis of HCC according to the American Association for the Study of Liver Diseases (AASLD) criteria. Current cirrhotic status of Child Pugh Class A (5-6
points), with no encephalopathy and/or clinically significant ascites (defined as requiring diuretics or paracentesis treatment). Child Pugh status must be calculated based on clinical and laboratory results during the screening period.
2. Baseline tumor tissue (newly obtained) must be available at screening. Patient must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution’s guidelines and requirements for such procedure.
3. Patients must be willing to undergo a new tumor biopsy during the study (6-9 weeks after start of study treatment, if medically feasible). For patients in the phase II part of the study, exceptions may be granted after documented discussion with Novartis. After a sufficient number of paired biopsies are collected, the decision may be taken to stop collecting the biopsies.
4. Patients must have received prior sorafenib treatment for HCC with documented progression during or after discontinuation of sorafenib treatment (for France only: patients must have received at least 8 weeks of prior sorafenib treatment), or are intolerant to sorafenib (defined as documented Grade 3 or 4 adverse events that led to sorafenib discontinuation).
5. Patients must be tested during screening for Hepatitis-B-Virus surface antigen (HbsAg) status. Patients are included in the study if they have adequately controlled hepatitis B, defined by:
• receiving a nucleoside analog anti-viral drug for 3 or more months, and
• serum hepatitis B virus (HBV) deoxyribonucleic acid (DNA) level of less than 100 IU/ml via polymerase chain reaction quantification assays prior to enrollment.
Other protocol-defined inclusion criteria may apply. |
|
| E.4 | Principal exclusion criteria |
1. Patient has received the following therapies prior to the first dose of study treatment:
• Previous systemic anti-cancer therapy (including therapeutic cancer vaccines and immunotherapeutics) other than sorafenib (sorafenib must be completed within > 2 weeks prior to the first dose of study treatment) or INC280.
• Previous locoregional therapy (e.g. hepatic arterial embolization, radio-frequency ablation, radiation therapy) if:
- administered after sorafenib treatment with the exception of palliative radiotherapy to a limited field, such as for the treatment of bone pain. Loco regional therapy for the focally painful liver tumor mass will be discussed on a case by case with Novartis.
- completed within 4 weeks prior to the dosing and, if present any related acute toxicity > grade 1.
2. Use of any live vaccines within 4 weeks of initiation of study treatment.
3. Major surgery within 2 weeks of the first dose of study treatment (mediastinoscopy, insertion of a central venous access device, and insertion of a feeding tube are not considered major surgery).
4. Participation in an interventional, investigational study within 2 weeks of the first dose of study treatment, unless agreed otherwise with Novartis.
5. Presence or history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis (i.e. affecting activities or daily living or requiring therapeutic intervention).
6. Presence of CTCAE grade ≥1 toxicity (except alopecia, peripheral neuropathy and ototoxicity, which are excluded if CTCAE grade ≥ 3) due to prior cancer therapy, unless agreed otherwise with Novartis.
to prior cancer therapy, unless agreed otherwise with Novartis.
7. Use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-CSF) ≤ 2 weeks prior start or study drug. An erythroid stimulating agent is allowed as long as it was initiated at least 2 weeks prior to the first dose of study treatment and the patient is on a stable dose.
8. History of severe hypersensitivity reactions to other mAbs.
9. Positive human immunodeficiency (HIV) testing at screening or Known history of testing positive for HIV or known acquired immunodeficiency syndrome.
10. Clinically significant pleural effusion that either required pleurocentesis or is associated with shortness of breath.
11. Patients receiving treatment with medications that are strong inducers of CYP3A4 and that cannot be discontinued at least 1 week prior to the start of treatment with INC280 and for the duration of the
study.
12. Unable to stop herbal/food supplements or treatments which are considered to be capable of significantly causing either PK or PD herb/food-drug interactions.
13. Active autoimmune disease or a documented history of autoimmune disease, including ulcerative colitis and Crohn's disease or any condition that requires systemic steroids or any immunosuppressive therapy, except vitiligo or resolved asthma/atopy that is treated with bronchodilators (e.g., albuterol).
14. Clinically significant, uncontrolled heart diseases.
• Unstable angina within 6 months prior to screening
• Myocardial infarction within 6 months prior to screening
• History of documented congestive heart failure (New York Heart Association functional classification III-IV)
• Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without antihypertensive medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior to screening
• Ventricular arrhythmias
• Supraventricular and nodal arrhythmias not controlled with medication
• Other cardiac arrhythmia not controlled with medication
• QTcF ≥ 450 ms (male patients), ≥ 460 ms (female patients) on the screening ECG (as mean of triplicate ECG)
Other protocol-defined exclusion criteria may apply. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase Ib part:
Safety: Incidence and severity of AEs and SAEs, including changes in laboratory values, vital signs and ECGs. Incidence of DLT during the first 2 cycles of treatment.
Tolerability: Dose interruptions, reductions, and dose intensity
Phase II part:
Overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1- Best overall response (BOR), duration of overall response (DOR), time to response (TTR), progression-free survival (PFS), time to progression (TTP), overall survival (OS) and for phase Ib, Overall response rate (ORR)
2- Safety: Incidence and severity of adverse events (AEs) and serious adverse events, including changes in laboratory parameters, vital signs and electrocardiograms (ECGs)
Tolerability: Dose interruptions, reductions and dose intensity
3- Best overall response (BOR), time to progression (TTP), cMET IHC score and GCN
4- Plasma/serum PK parameters (e.g., AUC, Cmax, Tmax)
Plasma/serum concentration vs. time profiles
5- TIL characterization &CD8 and PD-L1 protein expression |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| dose escalation and expansion |
|
| 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 | Yes |
| 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 | No |
| 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 | 2 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| 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 |
| Canada |
| China |
| Hong Kong |
| Japan |
| Korea, Republic of |
| Taiwan |
| United States |
| France |
| Germany |
| Italy |
|
| 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
|
>=80% of patients have died, been lost to follow-up, or been followed for >= 18 mth after the first dose of study treatment, and all patients have completed treatment and safety follow-up (FU).
OR
early study termination
OR
Another clinical study becomes available that can continue to provide study treatment, all patients ongoing transferred to that clinical study and all discontinued patients have completed safety FU. FU for disease progression and survival will not be performed. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 19 |
| E.8.9.2 | In all countries concerned by the trial months | 18 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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