Study of Vismodegib in Combination With Temozolomide Versus Temozolomide Alone in Patients With Medulloblastomas With an Activation of the Sonic Hedgehog Pathway

Sponsor

Centre Leon Berard (Other)

Overall Status

Terminated

CT.gov ID

NCT01601184

Collaborator

Ministry of Health, France (Other)

Enrollment

Locations

Arms

Duration (Months)

1.6

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety of vismodegib in combination with temozolomide (primary objective - phase I) and to estimate the efficacy of vismodegib in combination with temozolomide in adult patients with recurrent, progressive, or refractory medulloblastomas to standard therapy measured by the 6-month progression-free rate (phase II).

This study is an open-label Phase I/II, international, randomized.

38 patients will be included in the study.

Condition or Disease	Intervention/Treatment	Phase
Histologically Confirmed Medulloblastoma Activation of the Sonic Hedgehog (SHH) Pathway	Drug: vismodegib Drug: Temozolomide	Phase 1/Phase 2

Detailed Description

Secondary objectives are :

phase I : to collect preliminary results on the 6-month progression-free rate of the combination vismodegib + temozolomide

PHASE II

To estimate in the two study arms:

the objective response rate (Complete response + Partial Response according to WHO criteria) after 6 months of treatment
the duration of treatment response
the best overall response obtained during the study
the progression-free survival (PFS)
the time to progression (TTP)
the time to treatment failure (TTF)
In the combination arm (vismodegib + temozolomide): to further evaluate the safety of the combination.

Study Design

Study Type:

Interventional

Actual Enrollment :

24 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An International, Randomized, Open-label Phase I/II Study of Vismodegib in Combination With Temozolomide Versus Temozolomide Alone in Adult Patients With Recurrent or Refractory Medulloblastomas Presenting an Activation of the Sonic Hedgehog (SHH) Pathway

Study Start Date :

Jun 1, 2012

Actual Primary Completion Date :

Sep 1, 2017

Actual Study Completion Date :

Oct 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: combination of vismodegib with temozolomide In the first step of the study (Phase I), 9 adult patients with relapsing or refractory medulloblastoma will be randomized (randomization ratio 2:1) to receive - Arm A: the combination of vismodegib (150 mg/day continuously) with temozolomide (150 mg/m2 during Cycle 1 [day 1 to day 5/ 28 day-cycle] and 200 mg/m2 during subsequent cycles) (6 patients)	Drug: vismodegib Hedgehog pathway antagonist Dosage: 150 mg orally with or without food at the same time every day Drug: Temozolomide alkylating agent Dosage: Dose in Cycle 1 is 150 mg/m2 orally once daily for 5 days followed by 23 days without treatment. At the start of Cycle 2, the dose is escalated to 200mg/m2 orally once daily for 5 days Other Names: temodal
Active Comparator: temozolomide alone In the first step of the study (Phase I), 9 adult patients with relapsing or refractory medulloblastoma will be randomized (randomization ratio 2:1) to receive Arm B: temozolomide alone (150 mg/m2 day1 to day 5/ 28 day-cycle during Cycle 1 and 200 mg/m2 day 1 to day 5/ 28 day-cycle during subsequent cycles) (3 patients).	Drug: Temozolomide alkylating agent Dosage: Dose in Cycle 1 is 150 mg/m2 orally once daily for 5 days followed by 23 days without treatment. At the start of Cycle 2, the dose is escalated to 200mg/m2 orally once daily for 5 days Other Names: temodal
Other: vismodegib alone Considering the rarity of the disease, the few therapeutic options available and the promising results reported with vismodegib in adult medulloblastoma : the Sponsor will consider (on case by case basis) the enrolment of patients previously treated by temozolomide in a 3rd independent and parallel study arm	Drug: vismodegib Hedgehog pathway antagonist Dosage: 150 mg orally with or without food at the same time every day

Arm

Intervention/Treatment

Experimental: combination of vismodegib with temozolomide

In the first step of the study (Phase I), 9 adult patients with relapsing or refractory medulloblastoma will be randomized (randomization ratio 2:1) to receive - Arm A: the combination of vismodegib (150 mg/day continuously) with temozolomide (150 mg/m2 during Cycle 1 [day 1 to day 5/ 28 day-cycle] and 200 mg/m2 during subsequent cycles) (6 patients)

Drug: vismodegib

Hedgehog pathway antagonist Dosage: 150 mg orally with or without food at the same time every day

Drug: Temozolomide

alkylating agent Dosage: Dose in Cycle 1 is 150 mg/m2 orally once daily for 5 days followed by 23 days without treatment. At the start of Cycle 2, the dose is escalated to 200mg/m2 orally once daily for 5 days

Other Names:

temodal

Active Comparator: temozolomide alone

In the first step of the study (Phase I), 9 adult patients with relapsing or refractory medulloblastoma will be randomized (randomization ratio 2:1) to receive Arm B: temozolomide alone (150 mg/m2 day1 to day 5/ 28 day-cycle during Cycle 1 and 200 mg/m2 day 1 to day 5/ 28 day-cycle during subsequent cycles) (3 patients).

Drug: Temozolomide

Other Names:

temodal

Other: vismodegib alone

Considering the rarity of the disease, the few therapeutic options available and the promising results reported with vismodegib in adult medulloblastoma : the Sponsor will consider (on case by case basis) the enrolment of patients previously treated by temozolomide in a 3rd independent and parallel study arm

Drug: vismodegib

Hedgehog pathway antagonist Dosage: 150 mg orally with or without food at the same time every day

Outcome Measures

Primary Outcome Measures

To evaluate the safety of a fixed dose of vismodegib in combination with (phase I)temozolomide in adult patients with recurrent, progressive, or refractory to standard therapy medulloblastoma [during the first three months follow up]
number of severe toxicities occurring during the first 3 months of follow-up : Toxic death Grade 4 toxicity Any grade 3 AE leading to study treatment interruption for more than 7 days or discontinuation.
To estimate the efficacy of vismodegib in combination with temozolomide in adult patients with recurrent, progressive, or refractory to standard therapy medulloblastoma (phase II) [6 months after start of treatment]
the 6-month progression-free rate

Secondary Outcome Measures

To collect preliminary results on the 6-month progression-free rate of the combination vismodegib + temozolomide (phase I) [6 months after start of treatment]
measurement of progression free rate
To estimate in the two study arms the objective response rate after 6 months of treatment (phase II) [after 6 months of treatment]
measure by objective response rate
To estimate in the two study arms the duration of treatment response (phase II) [one year]
treatment response
To estimate in the two study arms the best overall response obtained during the study (phase II) [one year]
To estimate in the two study arms the progression-free survival (PFS)(phase II) [one year]
measure of progression free rate
To estimate in the two study arms the time to treatment failure (phase II) [one year]
frequency of adverse events based on the common toxicity criteria (CTC-AE-V4.0) grade [one year]
In the combination arm (vismodegib + temozolomide): to further evaluate the safety of the combination

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age ≥ 18 years
Patients must have histologically confirmed medulloblastoma (including posterior fossa primitive neuroectodermal tumor) for which no known curative therapy exists
Patients must have recurrent or refractory disease
Patients must have evidence of measurable disease or lesion in pre-inclusion MRI. Patients with measurable spinal disease are eligible. NB: Patients with complete resection for recurrence are not eligible.
Activation of the SHH pathway validated by IHC.
ECOG performance status 0, 1 or 2
Life expectancy ≥ 12 weeks
Patients must have normal organ and marrow function as defined below:

Neutrophils ≥ 1. 5 G/L Platelets ≥ 100 G /L Hemoglobin ≥ 10g/dL Creatinine clearance ≥ 50 mL/min (calculated by Cockcroft-Gault formula or MDRD formula for patients older than 65 years ) or serum creatinine within normal limits or less than 1.5 x upper limit of normal (ULN) Total bilirubin ≤ 1.5 ULN ALAT and ASAT ≤ 2.5 ULN Serum albumin ≥ 25 g/L.

Patients recovered from prior treatment-related toxicity (persistent treatment related toxicity <Grade 2 are allowed (NCI-CTCAE v4.0).
Prior therapy:

No prior hedgehog antagonist vismodegib or other antagonists of the hedgehog pathway, and no prior temozolomide treatment for patients to be randomized in Arm A or B. Patients previously treated with temozolomide are eligible for enrollment in study arm C on a case by case basis and following sponsor agreement More than 4 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas, 6 months after high dose therapy) or immunotherapy At least 3 months since prior craniospinal irradiation (≥ 23 Gy) At least 8 weeks since prior local irradiation to primary tumor At least 2 weeks since prior focal irradiation for symptomatic metastatic sites.

At least 1 week since prior colony-stimulating factors (e.g., G-CSF, GM-CSF, or erythropoietin)

Women of childbearing potential* are required to have a negative serum pregnancy test within 72 hours prior to study treatment initiation (i.e. Cycle 1 Day 1).

*: Female patients who meet at least one of the following criteria are defined as women of non-childbearing potential:

≥50 years old and naturally amenorrheic for ≥ 1 year Permanent premature ovarian failure confirmed by a specialist gynaecologist Previous bilateral salpingo-oophorectomy XY genotype, Turner's syndrome, or uterine agenesis Female patient who do not meet at least of the above criteria are defined as women of childbearing potential.

An embryo-fetal development study in rats has confirmed the teratogenic potential of vismodegib. Therefore, women of child-bearing potential and men must use two forms of effective contraception (including one barrier method- refer to Appendix 4 for acceptable method of contraception) at least 4 weeks prior to study entry, during the study period and for at least 24 months post-treatment for women and 2 months post-treatment for men. Prior to dispensing vismodegib, the investigator must confirm and document the patient's use of two contraceptive methods, dates of negative pregnancy test, and confirm the patient's understanding of the teratogenic potential of vismodegib.
Ability to understand and willingness to comply to follow-up visits.
Covered by a medical insurance (in countries where applicable)

Exclusion Criteria:

Tumor tissue sample not available for biological studies (from the initial diagnosis and/or relapse)
Pregnant or breastfeeding women are not eligible.
History of allergic reactions attributed to compounds of similar chemical composition to vismodegib.
Any contraindications to temozolomide treatment as per Temodal® SPC (see Appendix 5).
Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption. Patients must be able to swallow capsules.
Uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, or hypokalemia, defined as less than the lower limit of normal despite adequate electrolyte supplementation.
History of congestive heart failure.
History of ventricular arrhythmia requiring medication.
Congenital long QT syndrome.
Clinically significant unrelated systemic illness (e.g., serious infection or significant cardiac, pulmonary, hepatic, or other organ dysfunction) that would compromise the patient's ability to tolerate study treatment or would likely interfere with study procedures or results.
Patients using prohibited concomitant and/or concurrent medications (see section "Prohibited concomitant/concurrent treatments.)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CHU La Timone	Marseille	Bouches Du Rhône	France	13385
2	Institut Claudius Régaud (iuct-oncopole)	Toulouse	Haute-Garonne	France	31059
3	Hopital de La Pitié Salpétrière	Paris	Ile De France	France	75013
4	Institut de Cancérologie de l'Ouest - René Gauducheau	St Herblain	Loire Atlantique	France	44805
5	Hopital Central de Nancy	Nancy	Meurthe Et Moselle	France	54035
6	CHBS Hôpital du Scorff	Lorient	Morbihan	France	56322
7	CHRU de Lille	Lille	Nord	France	59037
8	Centre Léon Bérard	Lyon	Rhone	France	69373
9	Institut de Cancérologie de l'Ouest - Paul Papin	Angers		France	49933
10	Institut Bergonié	Bordeaux		France	33076
11	BELLARIA Ospedale	Bologna		Italy	40139
12	University of Turin	Torino		Italy	10126
13	Centre Hospitalier Universitaire Vaudois (CHUV)	Lausanne		Switzerland	CH-8091
14	University Hospital Zurich	Zurich		Switzerland	CH-8091
15	University College London Hospital - Mount Vernon Cancer Centre - Mount Vernon hospital	London		United Kingdom	London-NW1-2PG