A Phase I trial of figitumumab, an IGF-1R antibody, in children aged 1-12 years old with relapsed/refractory Solid Tumours - FOREST

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 48

Inclusion Criteria

1. Age = 1 years and = 12 years at the time of study entry.
2. Histological confirmation of solid extra-cranial malignancy at original diagnosis.
3. For expansion cohort only, patients must have measurable or clinically evaluable disease. Patients with neuroblastoma and other tumour types with disease assessable only by MIBG, Tc bone scan or BM aspirates/trephines are eligible.
4. Current disease status must be one for which there is no available curative therapy or therapy proven to prolong survival with an acceptable quality of life.
5. Performance Status:
•Lansky = 50%;
•Patients who are unable to walk because of paralysis, but who are able to sit upright unassisted in a wheelchair, will be considered ambulatory for the purpose of assessing performance score.
6. Adequate recovery from major surgery prior to study treatment.
7. No mitral valve regurgitation greater than trivial as determined by Doppler echocardiogram. Shortening of fraction =29%.(=35% for children <3 years). ECG without clinically significant abnormalities.
8. Must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy. Three weeks from previous chemotherapy (two weeks for vincristine and oral metronomic chemotherapy), four weeks from previous radiotherapy and six weeks from previous nitrosureas or myeloablative chemotherapy.
9. Adequate bone marrow function defined as:
•Platelet count =75,000/µL (unsupported during prior 72 hours, except patients with BM disease on expansion cohort)
•Haemoglobin =8.0 gm/dL (unsupported during prior 72 hours, except patients with BM disease on expansion cohort)
• Peripheral absolute neutrophil count (ANC) =1000/µL (without growth factor support during prior 72 hours)
•Patients with pancytopenia due to bone marrow metastasis will be eligible for study only for the Recommended Phase 2 expansion cohort and will not be evaluable for haematologic toxicity. These patients must not be refractory to red blood cell or platelet transfusions, and should be transfused to adequate levels as defined above prior to each cycle. In these patients, ANC must be above =500/µL without growth factor support during the prior 72 hours
10. Adequate renal function, defined as:
Serum creatinine ?1.5 x upper limit normal (ULN) for age. If above, creatinine clearance must be calculated with an accurate methodology (such as radioisotope GFR or inulin). If creatinine clearance is measured, GFR should be =60 ml/min/1.73m2.
11. Adequate liver function defined as:
•Total bilirubin (conjugated + unconjugated) = 1.5x the upper limit of normal (ULN) for age (except patients with liver metastasis or Gilbert’s syndrome = 2.5x ULN).
•Serum alanine aminotransferase (ALT) <2.5 × ULN (<5 x ULN for patients with liver metastasis)
•Serum aspartate aminotransferase (AST) <2.5 × ULN (<5 x ULN for patients with liver metastasis)
12. Males or females of reproductive potential may not participate unless they agree to use an effective contraceptive method, as described in the life style guidelines section, for the duration of study therapy and for 150 days after the last dose of Figitumumab. A negative pregnancy test must be obtained within 7 days prior to dosing in girls who are post-menarche (this aspect is unlikely to be relevant for most patients aged < 13 yrs).
13. All patients and/or their parents or legal guardians must sign a written informed consent. Assent, of the child, when appropriate,

Exclusion Criteria

1. Concurrent treatment with any anti-tumour agents.
2. Prior anti-IGF-1R therapy.
3. Patients with symptomatic brain metastases
4. Significant active cardiac disease including: cardiac shortening fraction < 29%; uncontrolled hypertension (Systolic BP and diastolic BP > 2 standard deviations (SD) above the mean for age); or serious cardiac arrhythmia(s).
5. Active infection.
6. Insulin-dependent diabetes mellitus as defined by glycosylated haemoglobin (Hgb A1c) = 6.5%) or use of high-dose steroids (>1mg/kg/day of prednisone or >5mg/m2/day of dexamethasone).
7. History of allergic reaction to IgG.
8. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results and, in the judgment of the Investigator.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To define the safety, tolerability, maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of the anti-IGF-1R antibody, figitumumab, in children (1-12 years old) with advanced solid tumours.;Primary end point(s): Safety, measured by assessment of adverse events and laboratory abnormalities (CTCAE Version 4.0: grade, timing, seriousness and relatedness);Secondary Objective: • To evaluate the pharmacokinetics (PK) of figitumumab in children.<br>• To monitor for any anti-drug antibody (ADA) response to figitumumab treatment. <br>• To evaluate the effect of figitumumab therapy on IGF-1 pathway serum biomarkers (i.e. total and free IGF-1, IGF-2, IGF-BP3, insulin and growth hormone).<br>• To provide preliminary indications of anti-tumour efficacy in a RP2D extension cohort and preliminary descriptive data on potential biomarkers (host and tumour) associated with drug handling and anti-tumour efficacy.<br>

Secondary Outcome Measures

Name	Time	Method

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