Study of Safety and Efficacy of EGFR-TKI EGF816 in Combination With cMET Inhibitor INC280 in Adult Patients With EGFR Mutated Non Small Cell Lung Cancer.
Study Details
Study Description
Brief Summary
The purpose of this study is to determine the maximum tolerated dose (MTD) / recommended phase 2 dose (RP2D) of nazartinib (EGF816) in combination with capmatinib (INC280) and to estimate the preliminary anti-tumor activity of nazartinib in combination with capmatinib in participants with advanced non-small cell lung cancer (NSCLC) with documented EGFR mutation.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1/Phase 2 |
Detailed Description
This study has been designed as a Phase Ib/II, multi-center, open-label study starting with a Phase Ib dose escalation part followed by a Phase II part. Oral nazartinib (once daily) and capmatinib (twice daily) will be administered on a continuous schedule until participant experiences unacceptable toxicity, progressive disease and/or treatment is discontinued at the discretion of the investigator or withdrawal of consent/opposition to use data/biological samples
In Phase Ib part, participants with NSCLC harboring EGFR activating mutations will be enrolled. At the end of the Phase Ib part, once the MTD or RP2D of nazartinib in combination with capmatinib has been declared, additional participants with NSCLC will be enrolled in the Phase II part in order to assess the preliminary anti-tumor activity of nazartinib in combination with capmatinib. Participants with locally advanced or metastatic NSCLC will be assigned into different groups according to their resistance mechanisms.
In an additional group (Phase II Group 5), preliminary anti-tumor activity of capmatinib as monotherapy will be evaluated in a two-stage design. This group will enroll 10 participants at the first stage with a futility analysis. At the second stage, additional participants will be enrolled provided that the futility analysis did not show any evidence of lack of efficacy of the capmatinib monotherapy.
Phase II Group 5 was intended to support study CINC280L12301. After thorough and careful assessment of study CINC280L12301 enrollment status, projected study completion timelines, and the changing clinical landscape, Novartis has made the decision to discontinue CINC280L12301 study. Importantly, this decision is not driven by safety concerns; no new safety signals have been observed in the study participants or in the ongoing capmatinib program. As such, Group 5 data is no longer needed and the new arm in study CINC280X2105C will not be opened as planned.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Phase IB part- NSCLC with EGFR activating mutations NSCLC participants who have previously documented EGFR mutation and progressed on EGFR TKI treatment |
Drug: Capmatinib
In Phase I part and Phase II (Groups 1 to 4), participants received capmatinib (twice daily) in combination with nazartinib (once daily).
Participants in Phase II Group 5, participants will start with capmatinib monotherapy (twice a day) and then will have the opportunity to continue with the combination of nazartinib (once a day) and capmatinib (twice a day).
Other Names:
Drug: Nazartinib
In Phase I part and Phase II (Groups 1 to 4), participants received capmatinib (twice daily) in combination with nazartinib (once daily).
Participants in Phase II Group 5, participants will start with capmatinib monotherapy (twice a day) and then will have the opportunity to continue with the combination of nazartinib (once a day) and capmatinib (twice a day).
Other Names:
|
| Experimental: Phase II- Group 1 (EGFRmut, any T790M, any MET, 2/4L antineoplastic, EGFR TKI resistant) NSCLC participants with previously documented activating EGFR mutation, with any T790M and MET dysregulation status, who received one to three lines of systemic antineoplastic therapy prior to study entry including one line maximum of first or second generation EGFR TKI and who progressed on this EGFR TKI treatment line. |
Drug: Capmatinib
In Phase I part and Phase II (Groups 1 to 4), participants received capmatinib (twice daily) in combination with nazartinib (once daily).
Participants in Phase II Group 5, participants will start with capmatinib monotherapy (twice a day) and then will have the opportunity to continue with the combination of nazartinib (once a day) and capmatinib (twice a day).
Other Names:
Drug: Nazartinib
In Phase I part and Phase II (Groups 1 to 4), participants received capmatinib (twice daily) in combination with nazartinib (once daily).
Participants in Phase II Group 5, participants will start with capmatinib monotherapy (twice a day) and then will have the opportunity to continue with the combination of nazartinib (once a day) and capmatinib (twice a day).
Other Names:
|
| Experimental: Phase II- Group 2 (EGFRmut, de novo T790M, any MET, 1/3L antineoplastic, EGFR TKI naïve) NSCLC participants harboring T790M mutation in de novo setting, irrespective of the activating mutation status who are treatment naïve or received maximum 2 lines of systemic antineoplastic therapy prior to study entry, but no therapy known to inhibit EGFR. |
Drug: Capmatinib
In Phase I part and Phase II (Groups 1 to 4), participants received capmatinib (twice daily) in combination with nazartinib (once daily).
Participants in Phase II Group 5, participants will start with capmatinib monotherapy (twice a day) and then will have the opportunity to continue with the combination of nazartinib (once a day) and capmatinib (twice a day).
Other Names:
Drug: Nazartinib
In Phase I part and Phase II (Groups 1 to 4), participants received capmatinib (twice daily) in combination with nazartinib (once daily).
Participants in Phase II Group 5, participants will start with capmatinib monotherapy (twice a day) and then will have the opportunity to continue with the combination of nazartinib (once a day) and capmatinib (twice a day).
Other Names:
|
| Experimental: Phase II- Group 3 (EGFRmut, T790M negative, any MET, 1L antineoplastic) NSCLC participants with previously documented EGFR activating mutation, T790M negative, and any MET status who never received any prior line of systemic antineoplastic systemic therapy prior to study entry. |
Drug: Capmatinib
In Phase I part and Phase II (Groups 1 to 4), participants received capmatinib (twice daily) in combination with nazartinib (once daily).
Participants in Phase II Group 5, participants will start with capmatinib monotherapy (twice a day) and then will have the opportunity to continue with the combination of nazartinib (once a day) and capmatinib (twice a day).
Other Names:
Drug: Nazartinib
In Phase I part and Phase II (Groups 1 to 4), participants received capmatinib (twice daily) in combination with nazartinib (once daily).
Participants in Phase II Group 5, participants will start with capmatinib monotherapy (twice a day) and then will have the opportunity to continue with the combination of nazartinib (once a day) and capmatinib (twice a day).
Other Names:
|
| Experimental: Phase II- Group 4 (EGFRmut, any T790M, any MET, 1L (treatment naïve) 2-3L antineoplastic) NSCLC participants with previously documented EGFR activating mutations and any T790M and MET status who were treatment naïve or failed maximum 2 prior lines of any systemic antineoplastic therapy for advanced disease. |
Drug: Capmatinib
In Phase I part and Phase II (Groups 1 to 4), participants received capmatinib (twice daily) in combination with nazartinib (once daily).
Participants in Phase II Group 5, participants will start with capmatinib monotherapy (twice a day) and then will have the opportunity to continue with the combination of nazartinib (once a day) and capmatinib (twice a day).
Other Names:
Drug: Nazartinib
In Phase I part and Phase II (Groups 1 to 4), participants received capmatinib (twice daily) in combination with nazartinib (once daily).
Participants in Phase II Group 5, participants will start with capmatinib monotherapy (twice a day) and then will have the opportunity to continue with the combination of nazartinib (once a day) and capmatinib (twice a day).
Other Names:
|
| Experimental: Phase II- Group 5 (EGFRmut, T790M-, MET GCN≥5, 2L, EGFR TKI resistant) NSCLC participants with previously documented EGFR activating mutation, T790M negative, acquired MET amplification who have progressed on one prior line of therapy for advanced/metastatic NSCLC disease. |
Drug: Capmatinib
In Phase I part and Phase II (Groups 1 to 4), participants received capmatinib (twice daily) in combination with nazartinib (once daily).
Participants in Phase II Group 5, participants will start with capmatinib monotherapy (twice a day) and then will have the opportunity to continue with the combination of nazartinib (once a day) and capmatinib (twice a day).
Other Names:
Drug: Nazartinib
In Phase I part and Phase II (Groups 1 to 4), participants received capmatinib (twice daily) in combination with nazartinib (once daily).
Participants in Phase II Group 5, participants will start with capmatinib monotherapy (twice a day) and then will have the opportunity to continue with the combination of nazartinib (once a day) and capmatinib (twice a day).
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Phase Ib: Number of participants with dose limiting toxicities (DLTs) [First 28 days of treatment]
Number of participants with DLTs in the Phase Ib part. A DLT is defined as an AE or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first 28 days of treatment with nazartinib in combination with capmatinib during the escalation part of the study
- Phase II Group 1, 2 and 3: Overall Response Rate per RECIST 1.1 [Up to approximately 3 years]
ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) determined by Blinded Independent Review Committee (BIRC) assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). ORR will be assessed in Group 1, 2 and 3 (Phase II part).
- Phase II Group 4: Number of participants with Adverse Events (AEs) and Serious AEs (SAEs) [Up to approximately 3 years]
Number of participants in Group 4 (Phase II part) with treatment-emergent AEs and SAEs
- Phase II Group 4: Number of participants with dose modifications [Up to approximately 3 years]
Number of participants with dose modifications, including dose interruptions and dose reductions in the Group 4 (Phase II part).
- Phase II Group 4: Dose intensity [Up to approximately 3 years]
Dose intensity is defined as the ratio of total dose received and actual duration in participants in Group 4 (Phase II part)
- Phase II Group 5: ORR per RECIST 1.1 based on investigator's assessment of INC280 monotherapy [Up to approximately 3 years]
ORR is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) of INC280 monotherapy determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). ORR will be assessed in participant in Group 5 (Phase II part)
Secondary Outcome Measures
- Phase Ib and Phase II Group 1, 2 and 3: Number of participants with dose modifications [Up to approximately 3 years]
Number of participants in Phase Ib and Phase II Groups 1, 2 and 3 with dose modifications, including dose interruptions and dose reductions
- Phase Ib and Phase II Group 1, 2 and 3: Dose intensity [Up to approximately 3 years]
Dose intensity is defined as the ratio of total dose received and actual duration in Phase Ib and Group 1, 2 and 3 (Phase II)
- Phase Ib and Phase II Group 4: Overall Response Rate (ORR) [Up to approximately 3 years]
ORR is defined as proportion of patients with best overall response of (PR+CR) determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). ORR will be assessed in Phase Ib and Phase II Group 4
- Phase Ib and Phase II Groups 1, 2, 3 and 4:Progression Free Survival (PFS) [From date of first dose to first documented disease progression or death, assessed up to approximately 3 years]
PFS is defined as time from date of first dose of study treatment to date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1. PFS will be assessed in Phase Ib and Group 1, 2, 3 and 4 (Phase II part)
- Phase Ib and Phase II Groups 1,2, 3 and 4: Time to Response (TTR) [From the date of the first dose to the date of first documented response, up to approximately 3 years]
TTR is defined as the time from the date of the first dose to the date of first documented response (CR or PR) determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). TTR will be assessed in Phase Ib and Group 1, 2, 3 and 4 (Phase II part).
- Phase Ib and Phase II Groups 1,2, 3 and 4: Duration of Response (DOR) [From date of first documented response to first documented disease progression or deaths, assessed up to approximately 3 years]
DOR is defined as the time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1. DOR will be assessed in Phase Ib and Group 1, 2, 3 and 4 (Phase II part)
- Phase Ib and Phase II Group 1, 2 3 and 4: Disease Control Rate (DCR) [Up to approximately 3 years]
DCR is defined as the proportion of patients with best overall response of CR, PR, or SD determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). DCR will be assessed in Phase Ib and Group 1, 2, 3 and 4 (Phase II part)
- Phase Ib and Phase II Groups 1,2, 3 and 4: Overall Survival (OS) [From date of first dose to death, assessed up to approximately 4 years]
OS is defined as the time from first dose of the study treatment to the date of death due to any cause. OS will be assessed in Phase Ib and Group 1, 2, 3 and 4 (Phase II part).
- Phase II Groups 1,2, 3 and 4: Area under the plasma concentration versus time curve (AUC) of nazartinib [Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1 (Cycle=28 days)]
The AUC values are based on the plasma concentration-time profile of nazartinib. AUC of nazartinib will be assessed for Group 1, 2, 3 and 4 (Phase II part)
- Phase II Groups 1,2, 3 and 4: Area under the curve (AUC) of capmatinib [Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1 (Cycle=28 days)]
The AUC values are based on the plasma concentration-time profile of capmatinib. AUC of capmatinib will be assessed for Group 1, 2, 3 and 4 (Phase II part)
- Phase II Groups 1,2, 3 and 4: Peak plasma concentration (Cmax) of capmatinib [Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1 (Cycle=28 days)]
The Cmax values are based on the plasma concentration-time profile of capmatinib. Cmax of capmatinib will be assessed for Group 1, 2, 3 and 4 (Phase II part)
- Phase II Groups 1,2, 3 and 4: Peak plasma concentration (Cmax) of nazartinib [Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1 (Cycle=28 days)]
The Cmax values are based on the plasma concentration-time profile of nazartinib. Cmax of nazartinib will be assessed for Group 1, 2, 3 and 4 (Phase II part)
- Phase II Groups 1,2, 3 and 4: Elimination half life (T1/2) of capmatinib [Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1 (Cycle= 28 days)]
The T1/2 values are based on the plasma concentration-time profile of capmatinib. T1/2 of capmatinib will be assessed for Group 1, 2, 3 and 4 (Phase II part)
- Phase II Groups 1,2, 3 and 4: Elimination half life (T1/2) of nazartinib [Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1 (Cycle=28 days)]
The T1/2 values are based on the plasma concentration-time profile of nazartinib. T1/2 of nazartinib will be assessed for Group 1, 2, 3 and 4 (Phase II part)
- Phase II Group 5: Duration of Response (DOR) for capmatinib monotherapy [From date of first documented response to the date of first documented disease progression or death, up to approximately 3 years]
DOR is defined as the time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1 for capmatinib monotherapy in Group 5 (Phase II)
- Phase II Group 5: Disease Control Rate (DCR) for capmatinib monotherapy [Up to approximately 3 years]
DCR is defined as the proportion of patients with best overall response of CR, PR, or SD determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) for capmatinib monotherapy in Group 5 (Phase II)
- Phase II Group 5: Progression Free Survival (PFS) for capmatinib monotherapy [Up to approximately 3 years]
Progression-free survival (PFS). PFS is defined as time from date of first dose of study treatment to date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1 for capmatinib monotherapy in Group 5 (Phase II)
- Phase II Group 5: Number of participants with dose modifications for capmatinib monotherapy as well as capmatinib in combination with nazartinib therapy [Up to approximately 3 years]
Number of participants with dose modifications, including dose interruptions and dose reductions in the Group 4 (Phase II part) for capmatinib monotherapy and capmatinib in combination with nazartinib
- Phase II Group 5: Dose intensity for capmatinib monotherapy as well as capmatinib in combination with nazartinib therapy [Up to approximately 3 years]
Dose intensity is defined as the ratio of total dose received and actual duration in participants in Group 5 (Phase II part) for capmatinib monotherapy as well as capmatinib in combination with nazartinib therapy
Eligibility Criteria
Criteria
Key Inclusion criteria:
-
Participants in Phase Ib and Phase II Groups 1 to 4 with histologically documented, locally advanced or recurrent (stage IIIB who are not eligible for combined modality treatment) or metastatic (Stage IV) NSCLC Participants in Phase II Group 5 must have stage IIIB/IIIC (not amenable to curative surgery, chemoradiation or radiation) or stage IV NSCLC
-
Participants in Phase Ib and Phase II Groups 1 to 4 must have locally documented EGFR mutation L858R and/or ex19del, or a characterized de novo EGFR T790M mutation (or other rare activating mutations that confer sensitivity to 1st and 2nd generation EGFR inhibitors (e.g. L861Q, G719X, S768I), or a characterized de novo EGFRT790M mutation.
-
Presence of at least one measurable lesion according to RECIST v.1.1
-
ECOG performance status ≤1
-
Patients must be screened for HBV. Patients who are either HBsAg positive or HBV-DNA positive must be willing and able to take antiviral therapy 1-2 weeks prior to 1st dose of EGF816 treatment and continue on antiviral therapy for at least 4 weeks after the last dose of EGF816.
-
Patients must be screened for HCV. Patients must have negative hepatitis C antibody (HCV Ab) or are HCV Ab positive but with an undetectable level of HCV-RNA. Note: patients with detectable HCV-RNA are not eligible for the study.
-
Phase Ib only: documented progression of disease according to RECIST v1.1 while on continuous treatment with EGFR TKI (e.g.: erlotinib, gefitinib or afatinib).
-
Phase II Group 1 (EGFRmut, any T790M, any c-MET, 2/4L antineoplastic, EGFR TKI resistant) only: Patients demonstrated a documented clinical benefit (CR (any duration), PR (any duration), or SD for at least 6 months) on prior EGFR TKI (e.g. erlotinib, gefitinib or afatinib, and subsequently demonstrated progression according to RECIST v1.1.
-
Phase II Group 2 (EGFRmut, de novo T790M, any c-MET, 1/3L antineoplastic, EGFR TKI naïve) only: Advanced NSCLC patients who have not been previously treated with any therapy known to inhibit EGFR and harbor de novo T790M mutation .
-
Phase II Group 3 (EGFRmut, T790M negative, any c-MET, 1L antineoplastic) only: patients must harbor an EGFR activating mutation and must be naïve from any line of systemic antineoplastic therapy in the advanced setting.
-
Phase II Group 4 (EGFRmut, any T790M, any c-MET, 1L (treatment-naïve), 2//3L antineoplastic): All patients must harbor an EGFR activating mutation and 2/3L patients must have failed (defined as intolerance to treatment or documented disease progression) a maximum of 2 prior lines of antineoplastic therapy in the advanced setting
-
Phase II Group 5 only: Histologically or cytologically confirmed diagnosis of NSCLC (excluding squamous cell carcinoma) with all the following:
-
EGFR mutations known to be associated with EGFR TKI sensitivity. This must be assessed as part of the participant standard of care by a validated test for EGFR mutations, as per local regulations. Exon 19 del, L858R, either alone or in combination with other EGFR sensitivity mutation assessed by a Clinical Laboratory Improvement Amendments (CLIA) certified USA laboratory or an accredited local laboratory outside the USA must be documented in the participant source documents before the participant can be consented for pre-screening for MET amplification status.
-
EGFR T790M negative status for participants who have progressed on first or second generation EGFR TKI, or third generation EGFR TKI other than osimertinib, as per tissue-based result from a CLIA-certified USA laboratory or an accredited local laboratory outside of the USA, by a validated test according to local regulations.
-
MET gene amplification defined as: Gene copy number (GCN) ≥ 5 per tissue-based result from a CLIA-certified USA laboratory or an accredited local laboratory outside of the USA by a test that is validated according to local regulations with results documented in the participant source documents.
-
Histological transformation from NSCLC into small cell lung cancer (SCLC) following previous EGFR TKI treatment are excluded.
- Participants must have progressed on one prior line of therapy either to first/second generation EGFR TKIs, osimertinib or other third generation EGFR TKIs for advanced/metastatic disease (stage IIIB/IIIC [not amenable to curative surgery, chemoradiation or radiation or stage IV NSCLC).
Key exclusion Criteria:
-
Phase Ib:
-
More than one previous treatment line with erlotinib, gefitinib or afatinib
-
Previous treatment with any investigational agent known to inhibit EGFR (mutant or wild-type)
-
Patients who have received more than three prior lines of antineoplastic therapies (including EGFR TKI) in advanced setting.
-
Phase II Group 1 (EGFRmut, any T790M, any c-MET, 2/4L antineoplastic, EGFR TKI resistant):
-
More than 3 prior lines of systemic antineoplastic therapies (including EGFR TKI) in the advanced setting
-
More than 1 previous treatment line with 1st or 2nd generation EGFR TKI (e.g. erlotinib, gefitinib, afatinib) in the advanced setting
-
Previous treatment with an investigational or marketed 3rd generation EGFR TKI (e.g. AZD9291, CO-1686, ASP8273, EGF816)
-
Previous treatment with an investigational or marketed agent known to inhibit EGFR (e.g. EGF monoclonal antibody therapy, dual TKI inhibitor).
-
Phase II Group 2 (EGFRmut, de novo T790M, any c-MET, 1/3L antineoplastic, EGFR TKI naïve):
-
More than two previous treatment lines of systemic antineoplastic therapies in the advanced setting
-
Previous treatment with an investigational or marketed agent that inhibits EGFR. EGFR inhibitors include (but not limited to) all generations of EGFR TKI (e.g.erlotinib, gefitinib, afatinib, AZD9291, CO-1686, ASP8273, EGF816) or other anti-EGFR or EGFR monoclonal antibody therapy or dual TKI inhibitors.
-
Phase II Group 3 (EGFRmut, T790M negative, any c-MET, 1L antineoplastic):
-
De novo EGFR T790M mutation identified by central assessment
-
Previous treatment with any systemic antineoplastic therapy in the advanced setting (NSCLC stage IIIB or IV. Patients who received only one cycle of antineoplastic therapy in the advanced setting are allowed).
-
Phase II Group 4 (EGFRmut, any T790M, any c-MET, 1/3L antineoplastic):
-
More than 2 prior lines of systemic antineoplastic therapies in the advanced setting
-
Previous treatment with an investigational or marketed 3rd generation EGFR TKI (e.g. AZD9291, CO-1686, ASP8273, EGF816)
-
Previous treatment with an investigational or marketed agent known to inhibit EGFR (e.g. EGF monoclonal antibody therapy, dual TKI inhibitor).
-
Previous treatment with a c-MET inhibitor or HGF-targeting therapy.
-
Patients with symptomatic brain metastases.
-
Phase II Group 5: Participants with symptomatic central nervous system (CNS) metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms.
-
Presence or History of another malignancy. Exception: Patients who have been disease-free for 3 years, or patients with a history of adequately treated in-situ carcinoma of the uterine cervix, completely resected basal or squamous cell carcinoma, non-melanomatous cancer of skin, history of stage IA melanoma that has been cured, are eligible.
For Phase II Group 5: Presence or history of a malignant disease other than NSCLC that has been diagnosed and/or required therapy within the past 3 years. Exceptions to this exclusion include completely resected basal cell and squamous cell skin cancers, and completely resected carcinoma in situ of any type.
-
Undergone a bone marrow or solid organ transplant.
-
Known history of human immunodeficiency virus (HIV) seropositivity (HIV testing is not mandatory).
For Group 5: Participants with known history of testing positive for human immunodeficiency virus (HIV) infection, and with a history of Acquired ImmunoDeficiency Syndrome (AIDS) defining opportunistic infections in the last 12 months prior to the first dose of study treatment must be excluded
-
Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use at the time of study entry except for control of brain metastases, topical applications, inhaled sprays, eye drops or local injections
-
Patients with clinically significant, uncontrolled cardiovascular disease
-
Presence or history of interstitial lung disease or interstitial pneumonitis
-
Patients have not recovered from all toxicities related to prior anticancer therapies to grade ≤1 (CTCAE v 4.03)
-
Participants in Phase Ib and Phase II Groups 1 to 4: Patients have out of range laboratory values defined as
-
Absolute Neutrophil Count (ANC) <1.5 x 109/L (1.5x103/µL)
-
Hemoglobin (Hb) <9 g/dL (90g/L)
-
Platelets (PLT) <75 x 109/L (75x103/µL)
-
Total bilirubin >1.5 x upper limit of normal (ULN).
-
AST and/or ALT >3 x ULN
-
Patients with liver metastasis may not be included if AST and/or ALT >5 xULN
-
Alkaline phosphatase (ALP) >5 xULN
-
Calculated creatinine clearance < 45mL/min (0.75 mL/sec)using Cockroft-Gault formula
-
Asymptomatic serum amylase or lipase > Grade 2
-
Serum amylase or serum lipase CTCAE grade ≥ 1 with signs and/or symptoms suggesting pancreatitis or pancreatic injury (e.g. elevated P-amylase, abnormal imaging findings of pancreas, etc)
Participants in Phase II Group 5 have out of range laboratory values defined as:
-
Absolute Neutrophil Count (ANC) <1.5 x 109/L (1.5 x 103/μL) without growth factor support
-
Hemoglobin (Hgb) <9 g/dL (90 g/L)
-
Platelets (PLT) <100 x 109/L (100 x 103/μL)
-
Total bilirubin >1.5 x upper limit of normal (ULN)
-
AST and/or ALT > 2.5 x ULN except for participants with liver metastasis, who may not be included if AST and/or ALT > 5 x ULN
-
Alkaline phosphatase (ALP) >5 xULN
-
Calculated creatinine clearance (using Cockcroft-Gault formula) < 50 mL/min
-
Asymptomatic serum amylase increase grade 1 and 2 are allowed if at the beginning of the study is confirmed to have no signs and/or symptoms suggesting pancreatitis or pancreatic injury
-
Serum lipase > ULN - Patients have the following laboratory values outside of the laboratory normal limits or cannot be corrected to within normal limits with supplements during screening: Potassium, Magnesium, Phosphorus, Total calcium (corrected for serum albumin)
Other protocol-defined inclusion/exclusion criteria may apply.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Massachusetts General Hospital Mass General | Boston | Massachusetts | United States | 02114 |
| 2 | Novartis Investigative Site | Melbourne | Victoria | Australia | 3000 |
| 3 | Novartis Investigative Site | Edmonton | Alberta | Canada | T6G 1Z2 |
| 4 | Novartis Investigative Site | Marseille Cedex 05 | France | 13885 | |
| 5 | Novartis Investigative Site | Heidelberg | Baden-Württemberg | Germany | 69126 |
| 6 | Novartis Investigative Site | Koeln | Nordrhein-Westfalen | Germany | 50937 |
| 7 | Novartis Investigative Site | Bologna | BO | Italy | 40138 |
| 8 | Novartis Investigative Site | Modena | MO | Italy | 41124 |
| 9 | Novartis Investigative Site | Perugia | PG | Italy | 06129 |
| 10 | Novartis Investigative Site | Seoul | Korea | Korea, Republic of | 05505 |
| 11 | Novartis Investigative Site | Oslo | Norway | NO 0424 | |
| 12 | Novartis Investigative Site | Singapore | Singapore | 119228 | |
| 13 | Novartis Investigative Site | Singapore | Singapore | 169610 | |
| 14 | Novartis Investigative Site | Barcelona | Catalunya | Spain | 08035 |
| 15 | Novartis Investigative Site | La Coruna | Galicia | Spain | 15006 |
| 16 | Novartis Investigative Site | Las Palmas De Gran Canarias | Las Palmas De Gran Canaria | Spain | 35016 |
| 17 | Novartis Investigative Site | Madrid | Spain | 28009 | |
| 18 | Novartis Investigative Site | Madrid | Spain | 28041 | |
| 19 | Novartis Investigative Site | Taipei | Taiwan ROC | Taiwan | 10041 |
Sponsors and Collaborators
- Novartis Pharmaceuticals
Investigators
- Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CINC280X2105C
- 2014-000726-37