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

Germ Cell Tumour Clinical Trial

— GAMMA  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01782339
• Other study ID #: 007755
• Secondary ID: 2010-022795-31
• Status: Completed
• Phase: Phase 2
• Start date: May 1, 2012
• Est. completion date: May 5, 2021

Study information

• Verified date: June 2024
• Source: Barts & The London NHS Trust
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 45
• Est. completion date: May 5, 2021
• Est. primary completion date: May 5, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Germ Cell Tumour
• Neoplasms, Germ Cell and Embryonal

Intervention

Drug:
• Combination Chemotherapy
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.

Locations

Country	Name	City	State
United Kingdom	St Bartholomew's Hospital	London

Sponsors (1)

Lead Sponsor	Collaborator
Barts & The London NHS Trust

Country where clinical trial is conducted

United Kingdom, 

References & Publications (9)

Bedano PM, Brames MJ, Williams SD, Juliar BE, Einhorn LH. Phase II study of cisplatin plus epirubicin salvage chemotherapy in refractory germ cell tumors. J Clin Oncol. 2006 Dec 1;24(34):5403-7. doi: 10.1200/JCO.2006.05.8065. — View Citation

Gerlinger M, Wilson P, Powles T, Shamash J. Elevated LDH predicts poor outcome of recurrent germ cell tumours treated with dose dense chemotherapy. Eur J Cancer. 2010 Nov;46(16):2913-8. doi: 10.1016/j.ejca.2010.07.004. Epub 2010 Aug 13. — View Citation

Haba Y, Williams MV, Neal DE, Ong JY, Ostrowski MJ, Ell PJ, Nargund V, Shamash J, Oliver RT. Stage migration and pilot studies of reduced chemotherapy supported by positron-emission tomography findings suggest new combined strategies for stage 2 nonseminoma germ cell tumour. BJU Int. 2008 Mar;101(5):570-4. doi: 10.1111/j.1464-410X.2007.07387.x. — View Citation

International Prognostic Factors Study Group; Lorch A, Beyer J, Bascoul-Mollevi C, Kramar A, Einhorn LH, Necchi A, Massard C, De Giorgi U, Flechon A, Margolin KA, Lotz JP, Germa Lluch JR, Powles T, Kollmannsberger CK. Prognostic factors in patients with metastatic germ cell tumors who experienced treatment failure with cisplatin-based first-line chemotherapy. J Clin Oncol. 2010 Nov 20;28(33):4906-11. doi: 10.1200/JCO.2009.26.8128. Epub 2010 Oct 18. — View Citation

Pectasides D, Pectasides M, Farmakis D, Aravantinos G, Nikolaou M, Koumpou M, Gaglia A, Kostopoulou V, Mylonakis N, Economopoulos T, Raptis SA. Oxaliplatin and irinotecan plus granulocyte-colony stimulating factor as third-line treatment in relapsed or cisplatin-refractory germ-cell tumor patients: a phase II study. Eur Urol. 2004 Aug;46(2):216-21. doi: 10.1016/j.eururo.2004.03.001. — View Citation

Shamash J, Powles T, Ansell W, Berney D, Stebbing J, Mutsvangwa K, Wilson P, Asterling S, Liu S, Wyatt P, Joel SP, Oliver RT. GAMEC--a new intensive protocol for untreated poor prognosis and relapsed or refractory germ cell tumours. Br J Cancer. 2007 Aug 6;97(3):308-14. doi: 10.1038/sj.bjc.6603865. Epub 2007 Jul 3. Erratum In: Br J Cancer. 2007 Oct 22;97(8):1188. Berney, Dan [added]. — View Citation

Shamash J, Powles T, Mutsvangwa K, Wilson P, Ansell W, Walsh E, Berney D, Stebbing J, Oliver T. A phase II study using a topoisomerase I-based approach in patients with multiply relapsed germ-cell tumours. Ann Oncol. 2007 May;18(5):925-30. doi: 10.1093/annonc/mdm002. Epub 2007 Mar 12. — View Citation

Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989 Mar;10(1):1-10. doi: 10.1016/0197-2456(89)90015-9. — View Citation

Theodore C, Chevreau C, Yataqhene Y, Fizazi K, Delord JP, Lotz JP, Geoffrois L, Kerbrat P, Bui V, Flechon A. A phase II multicenter study of oxaliplatin in combination with paclitaxel in poor prognosis patients who failed cisplatin-based chemotherapy for germ-cell tumors. Ann Oncol. 2008 Aug;19(8):1465-1469. doi: 10.1093/annonc/mdn122. Epub 2008 Apr 2. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective response rate		2 years
Secondary	Progression Free Survival		2 years
Secondary	Overall Survival		2 years
Secondary	Toxicity Level		2 years

External Links

•   Related Info