Primary:- To evaluate the efficacy of the combination of temozolomide with vincristine and irinotecan in children and adult patients with relapsed rhabdomyosarcoma as assessed by confirmed objective tumor response.Secondary:- To evaluate the safety…
ID
Source
Brief title
Condition
- Soft tissue neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint is defined as the proportion of patients who had
a documented complete or partial tumour response occurring after the first 2
cycles of treatment which must be confirmed by a follow-up objective tumour
assessment obtained within 4-5 weeks after the initial documentation.
Secondary outcome
Secondary efficacy endpoints are defined as follows:
- Duration of tumour response: the time from first documentation of objective
tumour response to the first objective or clinical documentation of progression
- Time to treatment failure: the time from the date of first treatment
administration to the first documentation of tumour progression,
discontinuation of study treatment before one year, or death, whichever occurs
first
- Time to tumor progression: the time from the date of first treatment
administration to the date of first objective or clinical documentation of
tumour progression or death due to any cause
- Overall survival: the time from the date of first treatment administration to
date of death
Background summary
Rhabdomyosarcoma is a soft tissue sarcoma derived from muscle precursor cells.
It is the commonest form of soft tissue sarcoma in children < 15yrs, accounting
for around 4% of paediatric malignancies and with a peak incidence in young
children < 5yrs.
Around 85% of children with rhabdomyosarcoma have localised disease at
presentation. The 3 yr event free survival of patients achieving complete
local control is 64% and 36% of patients who relapse can be salvaged. Among
patients experiencing relapse, the most frequent site of relapse is
locoregional (76%) with only 15% of patients having an isolated metastatic
recurrence. Survival after relapse is affected by several factors, the most
important being the type of recurrence, previous radiotherapy, time of relapse
and the initial tumour size. Survival after an isolated local relapse is around
50% at 3 years whereas it is only 13-14% at 3 years after a metastatic relapse.
This finding means that we urgently need new chemotherapy agents and/or
targeted agents for systemic treatment of rhabdomyosarcoma. Another key factor
is the ability to deliver good local therapy to locally relapsing tumours;
where patients have previously received radiotherapy, local therapy may be
limited to aggressive surgery. Surgical clearance may be aided by effective new
systemic therapies justifying the use of volumetric response of the target
lesions to the chemotherapy as the main evaluation criteria in the current
study.
The combination of Vincristin and Irinotecan is attractive as it has proven
it's activity in naive metastatic patients (window response rate 70%). In a
relapse setting response rate was 25-37%. Cytotoxicity of Irinotecan is
potentiated by Temozolomide and the toxicity profile of Temozolomide does not
show important overlap with the toxicity profiles of Irinotecan or Vincristine.
In preclinical studies (xenograft models of among others rhabdomyosarcoma)
complete responses were shown after combinations of non curative doses of each
drug suggesting therapeutic synergy. In successive pediatric phase I trials
dose limiting toxicities and maximum tolerated dose of Temozolomide and the
combination of Irinotecan, Temozolomide and Vincristine were determined. The
proposed trial will investigate the efficacy and tolerability of the addition
of Temozolomide (VIT) to the combination of Vincristine-Irinotecan (VI) in
refractory or recurrent rhabdomyosarcoma.
Study objective
Primary:
- To evaluate the efficacy of the combination of temozolomide with vincristine
and irinotecan in children and adult patients with relapsed rhabdomyosarcoma as
assessed by confirmed objective tumor response.
Secondary:
- To evaluate the safety, tolerability and efficacy of VIT and VI alone as
assessed by: duration of response, time to tumor progression, time to treatment
failure, overall survival and adverse event profile.
Study design
This is an international open-label, randomized, multicenter phase II study of
VIT and VI for the treatment of patients with recurrent rhabdomyosarcoma.
Intervention
Patients will be randomized 1:1 between treatments. Standard arm will be VI:
combination of Vincristin ( intravenous day 1 and 8) and Irinotecan
(intravenous day 1 - 5). Intervention arm will be the standard arm (VI) with
the addition of oral Temozolomide (day 1 - 5) (VIT). Both the standard and
intervention treatment arm will be given in a daycare setting. Patients will be
treated with cefixim day -2 till day 7 according to international guidelines.
Study burden and risks
The combination of Vincristin-Irinotecan is currently regularly applied in
patients with a relapsed rhabdomyosarcoma outside the setting of a prospective
therapeutic trial. This combination is chosen based on expected effectivity and
toxicity profile, where bone marrow suppression is not frequently found.
Important toxicity of Irinotecan is diarrhea, where chances for diarrhea are
reduced by the profylactic administration of ceftibuten. In case of diarrhea
this can usually be adequately treated with loperamide.
The addition of Temozolomide to Vincristin and Irinotecan was well tolerated in
earlier trials. Most important expected toxicity of Temozolomide is bone marrow
suppression, possibly causing the need for blood transfusions and risk for
infections.
All 3 drugs (Vincristin, Irinotecan and Temozolomide) can cause nausea; with
the profylactic use of antiemetics, nausea is generally well controlled.
rue Frédéric Combemale 3
Lille Cedex BP 307 - 59020
FR
rue Frédéric Combemale 3
Lille Cedex BP 307 - 59020
FR
Listed location countries
Age
Inclusion criteria
• Histologically or cytologically confirmed diagnosis of rhabdomyosarcoma
• Relapsed / progressive disease (previously shown respons to chemo-therapy)
• Measurable disease (defined as lesions that can be measured in 3 dimensions by medical imaging techniques such as CT or MRI).
• Age > 6 months and <=50 years
• Karnofsky performance status (PS) 70-100% (for patients > 12 years of age)
OR Lansky Play Score 70-100 % (for patients <= 12 years of age)
• Life expectancy >= 12 weeks
• Adequate bone marrow-, renal- and hepatic function (as defined in protocol)
• Fertile patients must use effective contraception
• Written informed consent of patient and/or parents/ guardians
Exclusion criteria
• Other malignancy, including secondary malignancy
• Concomitant anti-cancer treatment
• Pregnancy or breast feeding
• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
• Neuromuscular disorders (e.g. Charcot-Marie Tooth disease)
• Uncontrolled intercurrent illness or active infection
• Unavailable for medical follow-up (geographic, social or psychological reasons)
• Concurrent enzyme-inducing anticonvulsants (EIAC), including phenytoin, phenobarbital, or carbamazepine
• Concurrent administration of any of the following: rifampicin, voriconazole, itraco-nazole, ketoconazole, aprepitant
• Prior irinotecan or temozolomide administration
• Less then 3 weeks since prior myelosuppressive therapy (6 weeks for nitrosourea, 2 weeks for vincristine, vinorelbine, vinblastine and low-dose cyclophosphamide)
• Less than 3 weeks since prior radiation therapy to the site of any progressive lesion that will be identified as a target lesion to measure tumor response
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-023135-42-NL |
| ISRCTN | ISRCTN66172474 |
| CCMO | NL36401.018.11 |