Primary ObjectivesTo determine the pharmacodynamic effect of linsitinib in the tumourTo evaluate the safety and tolerability of linsitinibSecondary ObjectivesTo determine the clinical outcomeTo conduct pharmacokinetic assays with linsitinib…
ID
Source
Brief title
Condition
- Musculoskeletal and connective tissue neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Tumor and plasma biomarkers
Toxicity according to CTC version 3.0
Secondary outcome
Tumor measuremnt according to RECIST 1.1
PK data of linsitinib
Background summary
The most innovative development in ES has been the identification of the IGF1
receptor pathway deregulation, and early Phase I/II trials using agents that
target only IGF1R (R1507 and Figitumumab) have shown 10-15% partial response
rates and a number of patients with prolonged disease stabilisation [1, 2].
The antibody therapies have been well tolerated with some patients still being
maintained on therapy years after initial trial enrolment.
The reasons for the remarkable single agent efficacy observed in a small subset
of patients remains unknown, as is the relative lack of efficacy in the
majority of patients. There may be heterogeneity in response due to partial
signal pathway inhibition at the tumour level, inherent resistance in ES cells
or the presence of alternative pathway activation through IR-A receptor
signalling.
In terms of the former, the correlation of tumour response with high IGF-1
levels (>0.95ng/ml) maybe a reflection of variable (sub) therapeutic antibody
levels in some patients.
Overall, these agents are only going to result in tumour regression if the ES
cells undergo cell death, as these agents are not cytotoxic in themselves. Here
we aim to establish pharmacodynamic responses in ES tumours using functional
imaging
18FDG-PET-CT and repeat post treatment biopsies, toxicity and clinical outcome
to the dual anti-Insulin-like growth factor I / Insulin receptor kinase
blocking agent, linsitinib.
Study objective
Primary Objectives
To determine the pharmacodynamic effect of linsitinib in the tumour
To evaluate the safety and tolerability of linsitinib
Secondary Objectives
To determine the clinical outcome
To conduct pharmacokinetic assays with linsitinib treatment
Study design
International, multi-centre, single arm phase II study utilising Bayesian
analysis
Study burden and risks
2 tumor biopsies with associated risk
however chances of antitumor response are real given the experience with
similar drugs in this setting
Joint Research Office, Churchill Hospital, Old Road Block 60
Oxford OX3 7LE
GB
Joint Research Office, Churchill Hospital, Old Road Block 60
Oxford OX3 7LE
GB
Listed location countries
Age
Inclusion criteria
1. Histological or cytological confirmed original (no new biopsy required)
diagnosis of Ewing sarcoma, preferably with EWSR in situ hybridisation
break apart probe.
2. First, second or any relapse or refractory disease to conventional
treatment.
3. Current disease state for which there either is no known curative therapy
or therapy proven to prolong survival with an acceptable quality of life.
4. Has recovered from prior chemotherapy-related toxicity to <= grade 2.
5. Male or female, Age >= 18 and <=70 years.
6. Life expectancy of at least 4 months.
7. WHO performance score of 0-2.8. Must be able to take oral medication.
9. Is willing and able to comply with the protocol for the duration of the
study, and scheduled visits and examinations, including biopsies and
PET-CT scans.
10. Written (signed and dated) informed consent.
11. Tumour at biopsy accessible site; in the case of lung metastases,
accessible with VATS procedure.
12. Tumour progression documented with imaging in the 6 months prior to
study entry.
13. At least one measurable lesion on CT scan performed in past 14 days of
minimum size 1 cm and 18FDG uptake positive
14. Cardiac Ejection Fraction (Echocardiogram or MUGA) >=45%.
15. Fasting glucose <= 150 mg/dL (8.3 mmol/L) with no history of diabetes.
Concurrent use of non-insulinotropic anti-hyperglycaemic therapy for
diabetes is permitted if the dose has been stable for >= 4 weeks at the
time of enrolment.
16. Haematological and biochemical indices within the specified ranges as
below:
* Haemoglobin (Hb) >=9 g/dL (Previous transfusion is allowed)
* Absolute neutrophil count (ANC) >=1.0 x 109/L without growth factor
support
* Platelet count > 80.x 109/L (Previous transfusion is allowed)
* Bilirubin <1.5 times the upper limit of normal (ULN)
* Serum alanine aminotransferase (ALT) <2.5 x ULN for age and <= 5 x
ULN if liver metastasis
* Aspartate aminotransferase (AST) <2.5 x ULN for age
* Alkaline phosphatase <2.5 x ULN for age
* CPK <2.5 x ULN for age
* Serum creatinine <=1.5 x ULN for age
* Potassium, magnesium and calcium within normal limits
(supplementation and re-testing is permitted)
Exclusion criteria
Females: Pregnant or breast-feeding, or of childbearing potential unless
effective methods of contraception are used (see section 5.1 for
definition.) Males: Unless effective methods of contraception are used
(see section 5.1 for definition).
2. Significant active cardiac disease including: History (within last 6
months) of significant cardiovascular disease unless the disease is wellcontrolled.
Significant cardiac disease includes second/third degree
heart block; clinically significant ischemic heart disease; superior vena
cava (SVC) syndrome; poorly controlled hypertension; congestive heart
failure of New York Heart Association (NYHA) Class II or worse (slight
limitation of physical activity; comfortable at rest, but ordinary physical
activity results in fatigue, palpitation, or dyspnea).
3. History of arrhythmia (multifocal premature ventricular contractions
[PVCs], bigeminy, trigeminy, ventricular tachycardia, or uncontrolled
atrial fibrillation) that is symptomatic or requires treatment (>= grade 3),
left bundle branch block (LBBB), or asymptomatic sustained ventricular
tachycardia are not allowed. Patients with atrial fibrillation controlled by
medication are not excluded; uncontrolled high blood pressure (no
greater than 2 SD above the mean for age for SBP and DBP), unstable
angina, congestive heart failure, myocardial infarction within the previous
6 months, or serious cardiac arrhythmias.
LINES Confidential
LINES_Protocol_V4.0_13Jan2014 Protocol Template V2.0_20Mar2012
Page 11 of 71
4. Mean QTcF interval >= 450 msec based on analysis of screening visit and
pre-dose ECGs.
5. Use of drugs that have a known risk of causing Torsades de Pointes
(TdP) (*Torsades List* on www.azcert.org/medical-pros/druglists/
bycategory.cfm, see Appendix 4) within 14 days prior to registration.
6. Use of the potent CYP1A2 inhibitors ciprofloxacin and fluvoxamine within
7 days prior to registration. Linsitinib is primarily metabolized by
CYP1A2 and inhibitors/inducers of CYP1A2 could alter the
pharmacokinetics of linsitinib. Other less potent CYP1A2
inhibitors/inducers are not excluded.
7. Other psychological, social or medical condition, physical examination
finding or a laboratory abnormality that the Investigator considers would
make the patient a poor trial candidate or could interfere with protocol
compliance or the interpretation of trial results.
8. Any other active malignancy, with the exception of adequately treated
cone-biopsied in situ carcinoma of the cervix uteri and non-melanoma
skin lesions.
9. History of cerebrovascular accident (CVA) within 6 months prior to entry
that resulted in ongoing neurologic instability.
10. Patients with symptomatic brain metastases. Patients with previously
diagnosed brain metastases are eligible if they have completed their
CNS treatment and have recovered from the acute effects of radiation
therapy or surgery prior to the start of study medication, have
discontinued corticosteroid treatment for these metastases for at least 4
weeks, and are neurologically stable.
11. Major surgery within 4 weeks prior to study treatment.
12. Prior anti- IGF-1R treatment.
13. Treatment with any other investigational agent, or participation in another
clinical trial within 28 days prior to enrolment.
14. Patients who are known to be serologically postive for Hepatitis B, Hepatitis C or HIV
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 | EUCTR2012-000616-28-NL |
| ISRCTN | ISRCTN94236001NCTO2546544 |
| CCMO | NL51440.058.14 |