| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Intermediate- or high-risk myelofibrosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Myelofibrosis is a bone marrow disorder that disrupts body's normal production of blood cells resulting in extensive scarring in bone marrow |
|
| 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 | 19.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028537 |
| E.1.2 | Term | Myelofibrosis |
| 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. To evaluate the efficacy of vismodegib plus ruxolitinib compared with ruxolitinib plus placebo in patients with intermediate- or high-risk myelofibrosis (MF), as measured by spleen response rate at Week 24, determined by an Independent Review Committee (IRC)
2. To evaluate the efficacy of vismodegib plus ruxolitinib compared with
ruxolitinib plus placebo in patients with intermediate- or high-risk MF, as
measured by response rate (complete remission [CR] and partial
remission [PR]) at Week 24, determined by an IRC |
|
| E.2.2 | Secondary objectives of the trial |
1.To evaluate the efficacy of vismodegib plus ruxolitinib compared to placebo plus ruxolitinib measured by
•Spleen response rate at Weeks 24 and 48
•Response rate, defined as CR and PR at Weeks 24 and 48
•Overall response rate (ORR) at Weeks 24 and 48
•Anemia response rate at Weeks 24 and 48
•Symptom improvement at Weeks 24 and 48
•Duration of overall response (DOR)
•Improvement in bone marrow fibrosis at Weeks 24 and 48
•Progression-free survival (PFS)
•Fatigue improvement at Weeks 24 and 48
•Other symptom and impact improvements, Function and health-related quality of life improvement at Weeks 24 and 48
•Overall survival (OS)
2.To evaluate the safety of vismodegib plus ruxolitinib compared with ruxolitinib plus placebo in patients with intermediate or high-risk MF as evaluated by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), V4.0
3.To characterize the pharmacokinetics of vismodegib in patients with intermediate or high-risk MF
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Pathologically confirmed diagnosis of primary myelofibrosis (PMF), post−polycythemia vera (PV) MF, or post−essential thrombocythemia (ET) MF, according to the 2008 revised WHO criteria
- Intermediate-1, intermediate-2, or high risk according to the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Dynamic International Prognostic Scoring System (DIPSS)
Patients in the intermediate-1−risk group because of age alone (i.e., patients >= 65 years old with no other risk factors) are not eligible
- In the investigator’s judgment, requires treatment for MF
- Age >=18 years
- Life expectancy of >=6 months
- Peripheral blood blast count of <10%
- Palpable splenomegaly of >5 cm below the left costal margin
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2
- All non-hematological adverse events must have resolved to NCI CTCAE Grade <=2 prior to starting therapy
- Adequate hepatic and renal function:
. Total bilirubin =<2.0 × upper limit of normal (ULN), unless resulting from hemolysis and Gilbert’s Syndrome
. AST and ALT =<2.5 ×ULN (≤ 5 ×ULN if liver is involved by extramedullary hematopoiesis as determined by investigator)
. Serum creatinine =<1.5 × ULN and creatinine clearance >30 milliliter/minute
- Documented negative serum or urine pregnancy test for women of
childbearing potential and use of two forms of acceptable contraception,
including one highly effective contraceptive method plus a barrier
method with spermicide. Contraception must be used while the patient is
enrolled in the study and for 24 months after the last dose of vismodegib
- For men with female partners of childbearing potential, agreement to
use a latex condom and to advise their female partners to use an
additional method of contraception during the study and for 2 months or
3 months after the last dose of vismodegib, depending on the country
- Male patients must agree not to donate sperm during the study and for
at least 2 months or 3 months after the last dose of vismodegib,
depending on the country
- All patients must agree not to donate blood or blood products during
treatment and for 24 months after the last dose of vismodegib |
|
| E.4 | Principal exclusion criteria |
- Prior treatment with a Hedgehog (Hh) or Janus kinase (JAK) pathway inhibitor
- Treatment with strong CYP3A4 inhibitors/inducers within 28 days prior to Day 1
- Prior therapy for the treatment of intermediate- or high-risk MF within 28 days prior to Day 1
- Prior splenectomy or splenic irradiation
- Inadequate bone marrow reserve
- Patients with any history of platelet counts of < 50,000/microliter or absolute neutrophil count of < 500/microliter, except during treatment for myeloproliferative neoplasm (MPN) or treatment with cytotoxic therapy for any other reason
- Pregnant, lactating, or intending to become pregnant during the study
- Patients who refuse to potentially receive blood products and/or have a severe hypersensitivity to blood products
- Planned allogeneic bone marrow transplant during the study
- Known history of HIV
- Chronic active or acute viral hepatitis A, B or C infection
- Patients with suspected active or latent tuberculosis
- History of other malignancy that could affect compliance with the protocol or interpretation of results
- Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator’s judgment, precludes the patient’s safe participation in and completion of the study
- Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infections at study enrollment or any major episode of infection requiring treatment with intravenous antibiotics or hospitalization within 28 days prior to Day 1
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1.Spleen response rate at Week 24, as determined by an IRC using IWG-MRT revised response criteria
2.Response rate (PR and CR) at Week 24, as determined by an IRC using IWG-MRT revised response criteria
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1.Spleen response rate, determined according to IWG-MRT revised response criteria at Week 48 by an IRC and at Weeks 24 and 48 by the investigator
2.Response rate (PR and CR), determined according to IWG-MRT revised response criteria at Week 48 by an IRC and at Weeks 24 and 48 by the investigator
3.ORR (CR, PR, and clinical improvement) at Weeks 24 and 48, as determined by an IRC and the investigator using IWG-MRT revised response criteria
4.Anemia response rate at Weeks 24 and 48, as determined by the investigator using IWG-MRT revised response criteria
5.Symptom response rate from baseline to Weeks 24 and 48 as measured on a weekly basis on the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) diary
6.DOR, as determined by the investigator and an IRC using IWG-MRT revised response criteria or death from any cause during the study
7.Improvement in bone marrow fibrosis of at least one grade at Weeks 24 and 48, as determined by the investigator and independent pathology review using the European consensus grading system
8.PFS
9.Proportion of patients who achieve a >= 50% reduction in fatigue from baseline to Weeks 24 and 48 as measured on a weekly basis on the MPN-SAF TSS diary
10.Proportion of patients who achieve a >=50% reduction in other symptom and impact item scores from baseline to Weeks 24 and 48, as measured by the MPN-SAF
11.Proportion of patients who achieved a meaningful improvement on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) physical, role, social, and emotional function and health status/ health-related quality of life (HRQoL) scale scores from baseline to Weeks 24 and 48
12.OS
13.Incidence of adverse events
14.Incidence of serious adverse events and adverse events leading to vismodegib/placebo discontinuation or interruption
15.Changes in vital signs, physical findings, and in clinical laboratory results
16.Plasma total vismodegib, unbound vismodegib, and AAG at steady state determined from predose samples at timepoints |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-4: Weeks 24 and 48
5. Baseline to Week 24 and Week 48
6. From the first occurrence of a documented OR to the time of relapse or death (or up to 28 days after the last dose of study treatment)
7. Weeks 24 and 48
8. Time from date of randomization up to 28 days after the last dose of study treatment
9-11: Baseline to Week 24 and Week 48
12. From randomization to death from any cause (up to 28 days after the last dose of study treatment)
13-15: Up to 28 days after the last dose of study treatment
16. Pre-dose, at Week 6, Week 12, Week 24, Week 36, and Week 48
|
|
| 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 |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | Yes |
| 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 | 15 |
| 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 |
| France |
| Germany |
| Italy |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| The end of this study is defined as the timepoint at which all patients enrolled in the study have had either a minimum of 1 year of survival follow-up from the time of the study treatment completion/early discontinuation visit or have discontinued the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 7 |
| 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 | 7 |
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