This study has been transitioned to CTIS with ID 2023-504880-18-00 check the CTIS register for the current data. Primary• To determine the RP2D of crizotinib in combination with temsirolimus • To determine the safety and preliminary activity of…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Dose Limiting Toxicities (DLT) during the first cycle of crizotinib, in
combination with temsirolimus. For stratum 2; overall response rate for
stratum 1b and 3.
Secondary outcome
• Stratum 2 only: Overall response rate defined as the number of patients
achieving complete and partial responses by disease after 2 courses (8 weeks).
• Best overall response rate defined as best reported overall lesions response
at different evaluation time points from the start of study treatment until
disease progressionthe
Plasma concentration time profiles, PK parameters, including but not limited to
AUClast, AUCtau, Cmin, Cmax, Tmax, ,acc for crizotinib, temsirolimus .
• Progression-free survival (PFS)
• Overall survival
Biomarker endpoints
• Archival tumour sample and/or fresh frozen and/or embedded tumour sample
taken prior to enrolment will be analysed to show ALK, MET, ROS1 aberration
using next generation sequencing (NGS), FISH, immunohistochemistry (IHC).
• When available paired samples before and after 2 cycles of treatment will be
analysed to show inhibition of ALK and the PI3K/AKT pathways.
• When available paired bone marrow sample In patients with neuroblastoma
enrolled at the Royal Marsden Hospital before and after 2 cycles of treatment
will be stored for neuroblastic cells isolation and target inhibition studies
• PRP samples before and 4 hours after the start of drug(s) administration at
the beginning of cycle 1 and 2 will be analysed for target inhibition in PRP as
surrogate tissue
• Tumor cf-DNA will be analysed before, during and after treatment in order to
assess pre-treatment, in-treatment and post-treatment tumor genome alterations
and to compare those to the aberrations found in the primary tumor samples.
• For ALCL sequential blood samples will be assessed for minimal disseminated
disease by using NPM-ALK PCR as a marker for minimal residual disease and ALK
antibodies concentrations
Background summary
Crizotinib is a ALK, MET and ROS1 inhibitor that has proven to be effective and
is registered for ALK positive non-small cell lung carcinoma in adults. In
children, various tumors harbour ALK/MET/ROS1 aberrations, and children with
these tumours may potentially benefit from treatment with crizotinib.
Crizotinib as single-agent in the pediatric phase I dose-escalation study
showed favorable results in terms of toxicity, but variable results in terms of
efficacy, despite dose-escalation to much higher dosages than used in adults.
Very promising results were obtained in a small cohort of patients with ALCL,
although not all patients responded. Especially in patients with neuroblastoma
and ALK point-mutations responses were less promising than was anticipated, but
preclinical in-vitro and in-vivo studies have suggested that this may be
overcome with the combined use of crizotinib with a TORC 1/2 inhibitor.
In this study we therefore aim to evaluate combination therapy for different
strata. For stratum 1 we will tried to combine crizotinib with vinblastine,
based one earlier studies showing efficacy of vinblastine in the group of
relapsed, ALK positive ALCL patients. This combination showed considerable
toxicity. In collaboration with the pharmaceutical company, that has to meet
requirements by the FDA, this group of patients will be treated with crizotinib
monotherapy according to stratum 1b.For stratum 2 a combination of crizotinib
with temsirolimus will be given to patients with relapsed, ALK positive
neuroblastoma and rhabdomyosarcoma. Children who have other ALK- ROS or MET
positive tumors and who have no other treatment options, will be enrolled in a
separate stratum with crizotinib only (stratum 3).
Study objective
This study has been transitioned to CTIS with ID 2023-504880-18-00 check the CTIS register for the current data.
Primary
• To determine the RP2D of crizotinib in combination with temsirolimus
• To determine the safety and preliminary activity of single-agent crizotinib
in ALK, MET or ROS1 positive tumors
Secondary
• To study the preliminary activity of crizotinib in combination with
temsirolimus for relapsed or refractory ALK positive rhabdomyosarcoma or
neuroblastoma (stratum 2)
• To study pharmacokinetics of single-agent crizotinib, and crizotinib in
combination with r temsirolimus, and the potential drug-drug interactions
between crizotinib and temsirolimus
• To assess best overall respons and overall survival
• To assess the duration of response, time to progression and progression free
survival
Biomarker objectives
• To confirm target gene aberrations at enrollment in a central laboratory
• To study target activation at baseline
• To study target inhibition of ALK, AKT and mTOR pathway in all patients using
Platelets-Rich-Plasma (PRP) as surrogate tissue and tumor tissue when available.
• To show pharmacodynamic effects of crizotinib alone or in combination with
temsirolimus on ALK and PI3K/AKT pathways
• To study mechanisms of primary or acquired resistance in patients with
resistant or progressive disease
• To study minimal disseminated disease and ALK antibody titers in patients
with ALCL as a possible predictive marker
Study design
For stratum 2, this is an open label, non-randomized, two part, phase 1b
dose-finding study, with a dose escalation part followed by an expansion
cohort. For stratum 1b and 3 it is an open label, non-randomized phase 1b/II
study as an explorative cohort.
Intervention
In stratum 1, all patient will receive crizotinib twice daily (max 24 months)
In stratum 2, all patients will receive crizotinib twice daily in combination
with temsirolimus once weekly (max 8 month). Crizotinib will be dose escalated
according to the Escalation Method with Overdose Control (EWOC).
In stratum 3, all patients will receive crizotinib only (max 12 months).
Study burden and risks
All patients need to undergo a biopsy to obtain tumor material at the start of
the study when feasible and with acceptable risk. This will be standard of care
for most patients and will usually be done under anesthesia. Biopsies will be
repeated if possible at the end of cycle 2, or at the end of study, whichever
comes first for PD assessment. Radiological evaluation will be conducted every
2 months, consisting of either MRI/CT and/or MIBG; and may include bone marrow
aspirate and biopsy evaluation, depending on the entity of the tumor and its
localisation. PK assessment will be conducted at day 15 of cycle 1. Study
visits will be weekly (including blood draw and physical examination) during
the first 2 months of the study. From month 3 till month 12 (or end of study),
study visits will be done every other week. Patients still on study after 12
months will be scheduled monthly until 24 month. Risk associated with this
study are mainly the anticipated side-effects of crizotinib in combination with
temsirolimus . Crizotinib has been shown to be relatively safe in children in
a phase I study, but the number of treated patients is still limited. It also
has not been combined before with temsirolimus. Due to the potential
interaction between these drugs temsirolimus will be administered at 50% of the
recommended dose. Mainly liver toxicity and bone marrow depression is
anticipated. Considering the potential benefit of crizotinib especially in ALCL
and IMT, we think that the potential benefits of treatment study outweigh the
potential toxicity in these patients. In relapsed neuroblastoma and
rhabdomyosarcoma new treatment modalities are urgently required given the poor
outcome, which justifies enrolment in this study if informed consent is
obtained.
Wytemaweg 80
Rotterdam 3015 CN
NL
Wytemaweg 80
Rotterdam 3015 CN
NL
Listed location countries
Age
Inclusion criteria
Inclusion criteria
1b en 2:Histologically or cytologically confirmed diagnosis of
relapsed/refractory ALCL, including first relapse, NBL or RMS
3: Histologically confirmed diagnosis of other solid tumor or lymphomas other
than ALCL that is relapsed or refractory to standard therapy, or patients with
newly diagnosed IMT for whom surgery may not be feasible for close proximity to
vital structures, without prior tumor-shrinkage and no other feasible options
are available as per local standard of care.when stratum 1b is completed, ALCL
patients will be eligible to enroll into stratum 3
• Age at enrolment >=1 year of age and <= 21 years
• Lansky play score > 60%; or Karnofsky performance status > 60%.
Target gene aberration as defined as:
o stratum 1b: The t(2;5) translocation or rearrangement t(1;2), t(2;3), inv(2),
t(2;22). proven by ALK- immunohistochemistry, FISH or NGS
stratum 2: A point mutation in the kinase domain of ALK, An amplification of
the ALK gene,rearrangement in >15% of the tumor cells or An amplification of
the MET-gene,MET mutation, TFE3 rearrangement,
stratum 3:
o A point mutation in the kinase domain of ALK, or MET mutation
o An amplification of the ALK or MET gene,
o A ROS1 or TFE3 rearrangement in > 15% of the tumor cells
• Life expectancy >= 12 weeks
• Disease involvement :
o stratum 1b Measurable disease defined as at least one nodule with a longest
diameter greater than 1.5 cm (pediatric NHL response criteria)
stratum 2: For dose escalation measurable and non-measurable disease is
allowed; For dose expansion measurable disease is mandated, except for
neuroblastomas where MIBG or FDG avidity is sufficient
stratum 3:Measurable disease according to RECIST 1.1
Or, measurable disease as defined as at least one nodule with a longest
diameter greater than 1.5 cm
• Any previous systemic anticancer therapy must have been completed at least 2
weeks prior to initiation of study medication
• No prior therapy directly targeting ALK or ROS1 or MET
• No treatment with any other investigational drug within the past 2 weeks or
major surgery
Male and female patients of child-bearing potential must agree to use an
effective method for males and a highly effective method for females
Exclusion criteria
• Other serious illnesses or medical conditions, • Current uncontrolled
infection, • History of allergic reactions to the compounds or their solvents,
• Patients with untreated CNS metastases and/or primary CNS tumors and/or
meningeal, lymphoma involvement, defined as CNS3 status (patients with CNS2 are
eligible), • Concurrent use of drugs or foods that are known potent CYP3A4
inducers or inhibitors CYP3A4 substrates with narrow therapeutic indices as
well as medication with known QT*prolongation, •• Any of the following within
the 3 months prior to starting study treatment: myocardial infarction,
severe/unstable angina, coronary/peripheral artery bypass graft, congestive
heart failure or cerebrovascular accident including transient ischemic attack.
• Use of live vaccines within 30 days of first dosing
* Impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the, absorption of crizotinib (e.g., ulcerative diseases,
uncontrolled nausea, vomiting, diarrhea,, or malabsorption syndrome), • Not
able to comply with scheduled follow*up and with management of toxicity., • A
cardiac shortening fraction < 29%, • Ongoing cardiac dysrhythmias of NCI
CTCAE Grade >=2, uncontrolled atrial fibrillation of any, grade, or QTcF
interval >470 msec., • History of extensive disseminated/bilateral or known
presence of grade 3 or 4 interstitial, fibrosis or interstitial lung disease,
including a history of pneumonitis, hypersensitivity, pneumonitis, interstitial
pneumonia, interstitial lung disease, obliterative bronchiolitis, and,
pulmonary fibrosis, but not history of prior radiation pneumonitis., • No
evidence of active graft*vs*host disease (GVHD) and at least 3 months post*
allogeneic, HSCT. Must not receive GVHD prophylaxis., • For patients with
childbearing potential, a negative test for pregnancy and agreement to use,
effective contraceptive measures is required before entry on study.,• Spinal
cord compression unless treated with the patient attaining good pain control
and stable or recovered neurologic function.
• Prior malignancy (other than current malignancy): patients will not be
eligible if they have evidence of active malignancy (other than non-melanoma
skin cancer or localized cervical cancer, or localized and presumed cured
prostate cancer) within the last 3 years.
• Carcinomatous meningitis or leptomeningeal disease
Plus for stratum 2:, • Patients with neuroblastoma and bone marrow disease
only, are excluded.
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 |
|---|---|
| EU-CTR | CTIS2023-504880-18-00 |
| EudraCT | EUCTR2015-005437-53-NL |
| CCMO | NL55691.078.16 |