A Novel Single Arm Phase II Study for Relapsed Germ Cell Tumours With Poor Prognosis

Study Overview
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Brief Summary
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The treatment of germ cell tumours is considered to be one of the major successes in the area of cytotoxic chemotherapy. Even in patients who relapse after first line therapy, a durable remission rate of between 25% and 60% has been seen using further chemotherapy. In 1999, researchers at St Bartholomew's Hospital developed the GAMEC protocol (combination chemotherapy with filgrastim, actinomycin D, methotrexate, etoposide, cisplatin). Results from this study showed that 50% of patients with relapsed testicular cancer could be cured using this treatment. When we reviewed the individual patients it was clear that older patients (>35yrs) or patients with a raised Lactate Dehydrogenase (a blood test that monitors cancer activity), did not do as well. In addition, patients whose original tumour started in their chest (mediastinal germ cell tumour) have tended to do badly if they relapse. We have been developing a study for patients who fulfil at least one of these criteria. The GAMIO study (filgrastim, actinomycin D, methotrexate, irinotecan, oxaliplatin) has recently closed due to problems with high levels of toxicity from the irinotecan. GAMMA is a new study that will use paclitaxel instead of irinotecan and oxaliplatin instead of cisplatin. We expect that this treatment with oxaliplatin will be less damaging to the kidneys than cisplatin. Both oxaliplatin and paclitaxel and oxaliplatin and irinotecan have similar activity in relapsed patients in the phase II setting. We hope to improve on our previous results with this substitution and see if this will lead to an improvement in the cure rate of relapsed germ cell tumours with poor prognosis and reduce the side effects compared to our standard treatment. In addition, we do not expect any hearing damage and the treatment requires a shorter hospital stay.

Detailed Description
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Patients will receive a 4 drug combination chemotherapy in hospital over two nights. On the third day, the patient will receive an injection of pegfilgrastim. This stimulates the bone marrow to produce white blood cells and shortens the period of risk of serious infection. The treatment will be repeated every three weeks. This constitutes one cycle of treatment. We aim to give the patient four cycles of treatment over a total of twelve weeks. Before each cycle, the following will be conducted - physical examination, full blood count, urea + electrolytes, liver function tests, LDH, αFP, βHCG. Patients will have a FDG PET-CT scan at baseline, prior to cycle 2(approximately 1521 days after chemotherapy starts)and within 28 days of the last treatment, only if clinically indicated. On each cycle, serum creatinine should be measured 24 hours after the start of the methotrexate to exclude renal failure due to methotrexate. The following will be conducted at the end of treatment physical examination, full blood count, urea + electrolytes, liver function tests, LDH, αFP, βHCG. The patients will be monitored during chemotherapy and then monthly in the first year and two monthly in the second year. An interim analysis will be performed after 15 patients have completed treatment. If less than 9 responses are observed in this group, the study will be terminated. The final analysis will be performed after 43 patients have recruited, completed treatment and been followed for 24 months.

Official Title
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A Novel Single Arm Phase II Study for Relapsed Germ Cell Tumours With Poor Prognosis

Conditions
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Germ Cell Tumour

Intervention / Treatment
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* Drug: Combination Chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Germ Cell Tumour (GCT) Relapsed or progression on or following platinum-based chemotherapy (rising tumour markers or progressive disease on PET CT Scan prior to entering study) Neutrophil count >1.0x109/l Platelets >70x109/l Haemoglobin >100g/l (may be transfused) Glomerular filtration rate >40ml/min (determined by EDTA clearance or calculated creatinine clearance using the Cockcroft - Gault equation if unable to perform EDTA clearance) Males and females aged 16-65 years a) Male patients must have IGCCCG2 prognostic score, low to very high Patients must be sterile or agree to use adequate contraception during the period of therapy ECOG Performance status 0-3 Able and willing to give written informed consent and comply with the protocol study procedures. Exclusion Criteria: Other malignancy except basal cell carcinoma Significant co-morbidity likely to make delivery of this treatment unsafe Currently enrolled in any other investigational drug study Previous chemotherapy with oxaliplatin, methotrexate or Actinomycin D Patients who have peripheral neuropathy with functional impairment

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination Chemotherapy<br>4 cycles of: Day 1 Actinomycin D 1mg/m2, Paclitaxel 80mg/m2, Methotrexate Day 4 Oxaliplatin 100mg/m2 Pegfilgrastim 6mg Day 8* Paclitaxel 80mg/m2 Day 15 Paclitaxel 80mg/m2 *Day 8 will be omitted for the first three patients treated in this study and will be given at the end of treatment in a fifth cycle where Paclitaxel 80mg/m2 will be administered on Days 1, 8, 15 and 22. Before adding the extra Paclitaxel 80mg/m2 dose on day 8 the safety data for these patients will be reviewed by a DMC. NB This 5th cycle for patients 1-3 has been included to ensure that the four 'missed doses of paclitaxel are not omitted from the patients treatment regimen. Cycles 1-4 are 21 days cycles; Cycle 5 (for the first three patients only) is a 28 day cycle. | Drug: Combination Chemotherapy<br>* 4 cycles of: Day 1 Actinomycin D 1mg/m2, Paclitaxel 80mg/m2, Methotrexate Day 4 Oxaliplatin 100mg/m2 Pegfilgrastim 6mg Day 8* Paclitaxel 80mg/m2 Day 15 Paclitaxel 80mg/m2 *Day 8 will be omitted for the first three patients treated in this study and will be given at the end of treatment in a fifth cycle where Paclitaxel 80mg/m2 will be administered on Days 1, 8, 15 and 22. Before adding the extra Paclitaxel 80mg/m2 dose on day 8 the safety data for these patients will be reviewed by a DMC. NB This 5th cycle for patients 1-3 has been included to ensure that the four 'missed doses of paclitaxel are not omitted from the patients treatment regimen. Cycles 1-4 are 21 days cycles; Cycle 5 (for the first three patients only) is a 28 day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate |  | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival |  | 2 years | 
| Overall Survival |  | 2 years | 
| Toxicity Level |  | 2 years |