| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
To investigate RO5126766 single agent activity in patients with metastatic or advanced solid tumor.
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10007050 |
| E.1.2 | Term | Cancer |
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| 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 |
Part I of the study (Dose Escalation):
- To determine the Maximum Tolerated Dose (MTD) and the Dose Limiting Toxicities (DLT) of RO5126766 administered on an oral continuous daily schedule.
Part II of the study (Expansion Cohort):
- To investigate RO5126766 single agent activity in patients with metastatic or advanced solid tumor.
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| E.2.2 | Secondary objectives of the trial |
1. To determine the safety and tolerability profiles of RO5126766;
2. To determine the pharmacokinetic (PK) of RO5126766;
3. To determine the pharmacodynamic (PD) effect of RO5126766 in tumor by pERK inhibition and PET imaging, and in surrogate tissues with skin biopsy and peripheral blood samples;
4. To explore the PK/PD relationship and relate this to any disease response obtained;
5. To define a Minimal Biological Dose (MBD) and an Optimal Biological Dose (OBD).
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Roche Sample Repository Research Project in association with protocol NO21895: Open-label, multicenter, dose-escalation Phase I/II study to evaluate safety, pharmacokinetics and activity of RO5126766, a dual Raf and MEK inhibitor, administered orally as monotherapy in patients with advanced tumors.
Protocol NO21895RG version A dated July 3, 2008
Objectives : To obtain a single blood sample from consenting patients enrolled in associated study NO21895 for pharmacogenetic and genetic research analysis. |
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| E.3 | Principal inclusion criteria |
1. Patients must have histologically or cytologically confirmed diagnosis of cancer which is not amenable to curative therapy (i.e., advanced and/or metastatic disease).
•Part I (Dose Escalation): Patients with any tumor type or histology may be included.
•Part II (Expansion Cohort): Patients with the following tumor types will be enrolled: malignant melanoma, pancreatic cancer, non small cell lung cancer. If emerging Part I data suggest that a particular tumor type or specific tumor histology might be responsive to treatment, then this tumor type or histology would be considered as preferred disease for inclusion.
2. Prior Therapy :
•The number of prior systemic therapies given for metastatic disease will not be limited (for both Part I and Part II of the study).
3. Age ≥ 18 years.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
5. Life expectancy of ≥12 weeks.
6. Disease measurability:
•Part I (Dose Escalation): Patients must have a measurable (as per RECIST criteria) and/or evaluable disease (e.g., cytologically or radiologically detectable disease such as ascites, peritoneal deposits, or lesions which do not fulfill RECIST criteria for measurable disease).
•Part II (Expansion Cohort): Patients must have at least one measurable disease lesion as per the RECIST criteria.
7. Patient ability to comply with the collection of tumor biopsies (at baseline, on day 15 of cycle 1, and at the time of disease progression, complete/partial response, or stable disease lasting for more than 4 months) for those eligible for that evaluation (mandatory for part II).
8. Adequate bone marrow function as defined by: ANC of ≥1.5 x 10 exp9/L, platelet count of ≥100.0 x 10 exp9/L, and hemoglobin of ≥9 g/dL.
9. Adequate liver function, as determined by: Serum total bilirubin ≤1.5 ULN, AST and ALT ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases); AP < 2.5 x ULN (< 5x ULN if liver metastases). There is no upper limit for alkaline phosphatase (AP) if elevations are due exclusively to bone metastases or if the patient has prostate cancer.
10. Adequate renal function assessed by at least one of the following: 1) Serum creatinine ≤ 1.5 xULN or 2) creatinine clearance estimate of ≥60 mL/min in male and ≥50 mL/min in female (as calculated according to Cockroft-Gault formula).
11. Serum calcium (corrected for albumin level) ≤1.0 x ULN.
12. INR and PTT ≤ 1.5.
13. Signed informed consent.
14. Patient ability to comply with protocol requirements (visits and assessment schedules) and willingness to submit to blood sampling for the PK and PD analyses.
15. Female patients must be postmenopausal (12 months of amenorrhea), surgically sterile or they must agree to use a physical method of contraception. Oral or injectable contraceptive agents can not be the sole method of contraception. Male patients must be surgically sterile or agree to use a barrier method of contraception.
16. Female patients of child-bearing potential must have a negative urine pregnancy test within the seven days prior to the first study drug administration. |
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| E.4 | Principal exclusion criteria |
1. Patients with the inability to swallow oral medications or impaired gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease.
2. Patients with known (past or present) Central Nervous System (CNS) metastases.
3. Patients with history of gallbladder disorder or complication including cholelithiasis.
4. Prior chemotherapy, radiotherapy (other than short cycle of palliative radiotherapy for bone pain), or immunotherapy within 28 days of first receipt of study drug (within 6 weeks for nitrosoureas and mitomycin C). Hormone therapy within 14 days of first receipt of study drug, with exception of prostate cancer if indicated.
5. Prior toxicities from chemotherapy or radiotherapy which have not regressed to Grade ≤1 severity (NCI-CTCAE version 3.0).
6. Prior corticosteroids as anti-cancer therapy within a minimum of 14 days of first receipt of study drug.
7. Treatment with any investigational agent within 28 days of first receipt of study drug.
8. Patients with acute or chronic infection. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding or any other medical condition that, in the opinion of the investigator, contraindicates the use of an investigational drug, or will impose excessive risk to the patient. Examples of such medical conditions include significant cardiovascular disease (such as NYHA Class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina) or severe obstructive pulmonary disease .
9. Patients with HIV, HBV and HCV infection.
10. Patients exposed to CYP3A4 inhibitors within 7 days prior to the first dose and CYP3A4 inducers 14 days prior to the first dose (see Appendix°5 table for CYP3A4 inducers and inhibitors).
11. History of any bowel disease including abdominal fistula, gastro-intestinal perforation, and diverticulitis.
12. Major surgery within 28 days of first receipt of study drug.
13. Pregnant or lactating women.
14. Patients with altered mental status or psychiatric disorder that, in the opinion of the investigator, would preclude a valid patient informed consent.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| This study is primarily designed in Part I to characterize DLTs and to determine the MTD (maximum tolerated dose) and OBD (optimal biological dose) of RO5126766. Response to treatment according to the RECIST criteria (complete/partial responses: CR/PR, stable disease: SD, for definition see Appendix 4 RECIST). In Part II of the study, safety, tolerability, and anti-tumor activity will be further assessed in the MTD and OBD. The Objective Response Rates (Objective Response Rate: CR+PR) and Clinical Benefit Rates (CBR: CR+PR+SD > 4 months), as well as median Progression Free Survival (PFS measured from the day of first administration of RO5126766 until the date of first documented disease progression or death by any cause) will be calculated for the MTD and OBD to evaluate the most likely effective dose for all tumor types combined and by tumor type. |
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| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| MTD (maximum tolerated dose) and OBD (optimal biological dose); Biomarker analysis |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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 | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 26 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 30 |
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