Carboplatin-Etoposide Combination in Hormone-Resistant Prostate Cancers

Prostate Cancer Clinical Trial

Official title:

Phase II Multicenter Study Evaluating the Efficacy of Carboplatin-Etoposide Combination in Hormone-resistant Prostate Cancers With Neuroendocrine Differentiation.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00973882
• Other study ID #: CARBETOP
• Secondary ID: ET2005-005
• Status: Completed
• Phase: Phase 2
• First received: September 7, 2009
• Last updated: November 2, 2011
• Start date: April 2005
• Est. completion date: January 2010

Study information

• Verified date: November 2011
• Source: Centre Leon Berard
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Direction Générale de la Santé
• Study type: Interventional

Clinical Trial Summary

The aim of our study is to assess the efficacy and toxicity of a chemotherapy regimen combining carboplatin and etoposide in patients with metastatic hormone-resistant prostate cancer and neuro-endocrine differentiation. Eligible patients are treated with the combination of carboplatin AUC4 on day 1 and etoposide 100 mg/m2 on day 1, day 2 and day 3 repeated every 3 weeks for a maximum of 6 cycles. Efficacy endpoints include Prostate Specific Antigen (PSA) and neuro-endocrine marker response (defined as a 50% or greater decrease from baseline serum values), objective response rate (according to RECIST criteria), and toxicity.

Description:

Neuro-endocrine differentiation is observed in the evolution of hormone-resistant prostate cancer. The aim of our study is to assess the efficacy and toxicity of a chemotherapy regimen combining carboplatin and etoposide in patients with metastatic hormone-resistant prostate cancer and neuro-endocrine differentiation. To be eligible, patients must have either circulating neuro-endocrine markers (Chromogranin A: CgA, Neuron Specific Enolase: NSE)and/or visceral metastases. Eligible patients are treated with the combination of carboplatin AUC4 administered on day 1 and etoposide 100 mg/m2 given on day 1, day 2 and day 3 and repeated every 3 weeks for a maximum of 6 cycles. The primary objective of the study is to assess objective response to the carboplatin - etoposide combination (according to RECIST criteria for lesions and defined as a 50% or greater decrease from baseline serum values for PSA and neuro-endocrine markers). Secondary objectives include evaluation of toxicity, duration of response, progression-free-survival and overall survival.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: January 2010
• Est. primary completion date: July 2009
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histological evidence of prostate adenocarcinoma

• Metastatic disease, either measurable (lymph nodes, hepatic lesion, pulmonary lesions with longest diameter > or = 1 cm on spiral scan), or non measurable (bone metastasis)

• Patients must:

• Have received hormonal therapy via surgical or chemical castration (LH-RH agonist) with or without anti-androgens. Anti-androgen withdrawal is recommended before inclusion, with an off-treatment period of at least 4 weeks. LH-RH agonist treatment must be continued.

• Have a relapse or disease refractory to hormonal treatment (defined by a testosterone level < 0.5 µg/ml)

• Have neuroendocrine progression defined, whatever the PSA level, as:

• NSE and/or Chromogranin A > 1.5 x upper limit of normal (ULN) with or without visceral metastases (liver, lung, lymph node)

• No increase of NSE or Chromogranin A, but visceral metastases (either hepatic, pleuro-pulmonary, or nodal) with cytological or histological confirmation of the presence of an undifferentiated or neuro-endocrine component of prostatic origin

• Prior treatment by radiotherapy is allowed but radiation therapy must have been completed for at least 4 weeks before inclusion and irradiated areas must not represent more than 25% of marrow reserves

• Prior treatment by estramustine is allowed but must have been stopped at least 4 weeks before inclusion

• Age> or = 18 years

• Life expectancy> or = 3 months

• Karnofsky index> or = 50%

• Adequate haematological function: neutrophils> or = 1.5 G/l, platelets> or = 100 G/l, haemoglobin> or = 8 g/dl. Use of erythropoietin is allowed.

• Adequate liver function: bilirubin level within the institution's normal range, AST and ALT< or = 1.5 ULN

• Adequate renal function: creatinine clearance> or = 40 ml/min (Gault and Cockroft method)

• Signed written informed consent.

Exclusion Criteria:

• Patients having no> 1.5 x ULN increase of at least one neuro-endocrine marker (NSE or chromogranin A) and no cytological or histological (undifferentiated or neuro-endocrine type) evidence of visceral metastasis (hepatic, pleuro-pulmonary, or nodal)

• History of other malignancies, other than curatively treated basal cell skin carcinoma or any other curatively treated cancer with no sign of recurrence within 5 years

• Symptomatically uncontrolled brain metastasis

• Interstitial radiation therapy (using strontium or samarium) within the previous 3 months

• Prior treatment with platinum salts or etoposide. Other chemotherapy regimens are allowed provided that the last dose has been administered> or = 4 weeks prior to inclusion.

• Concomitant treatment with other anti-cancer drugs, except corticoid or LH-RH agonist injections

• Peripheral neuropathy> or = 2 (NCI-CTCAE)

• Uncontrolled progressive thrombo-embolic disease

• Uncontrolled infection

• Medical history of acute myocardial infection or uncontrolled angina pectoris, or hypertension or uncontrolled arrythmia

• Inclusion in another clinical trial

• Impaired follow-up for social, geographical, familial or psychological reasons

• Any other unstable disease.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Prostate Cancer
• Prostatic Neoplasms

Intervention

Drug:
• Carboplatin
Carboplatin AUC4 on day 1 repeated every 3 weeks for a maximum of 6 cycles
• Etoposide
Etoposide 100 mg/m2 on day 1, day 2 and day 3 repeated every 3 weeks for a maximum of 6 cycles

Locations

Country	Name	City	State
France	Centre François Baclesse	Caen
France	Hôpital Henri Mondor	Créteil
France	Centre Georges François Leclerc	Dijon
France	Centre Hospitalier Départemental Les Oudairies	La Roche Sur Yon
France	Centre Leon Berard	Lyon
France	Institut Paoli Calmette	Marseille
France	Centre Val d'Aurelle	Montpellier
France	Fondation Hôpital Saint-Joseph	Paris
France	Hopital Européen Georges Pompidou	Paris
France	Institut Curie	Paris
France	Hopital Foch	SURESNES Cedex

Sponsors (1)

Lead Sponsor	Collaborator
Centre Leon Berard

Country where clinical trial is conducted

France, 

References & Publications (21)

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Aumüller G, Leonhardt M, Janssen M, Konrad L, Bjartell A, Abrahamsson PA. Neurogenic origin of human prostate endocrine cells. Urology. 1999 May;53(5):1041-8. — View Citation

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Calvert AH, Newell DR, Gumbrell LA, O'Reilly S, Burnell M, Boxall FE, Siddik ZH, Judson IR, Gore ME, Wiltshaw E. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol. 1989 Nov;7(11):1748-56. — View Citation

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Maksymiuk AW, Jett JR, Earle JD, Su JQ, Diegert FA, Mailliard JA, Kardinal CG, Krook JE, Veeder MH, Wiesenfeld M, et al. Sequencing and schedule effects of cisplatin plus etoposide in small-cell lung cancer: results of a North Central Cancer Treatment Group randomized clinical trial. J Clin Oncol. 1994 Jan;12(1):70-6. — View Citation

Miller AA, Herndon JE 2nd, Hollis DR, Ellerton J, Langleben A, Richards F 2nd, Green MR. Schedule dependency of 21-day oral versus 3-day intravenous etoposide in combination with intravenous cisplatin in extensive-stage small-cell lung cancer: a randomized phase III study of the Cancer and Leukemia Group B. J Clin Oncol. 1995 Aug;13(8):1871-9. — View Citation

Moore MJ, Osoba D, Murphy K, Tannock IF, Armitage A, Findlay B, Coppin C, Neville A, Venner P, Wilson J. Use of palliative end points to evaluate the effects of mitoxantrone and low-dose prednisone in patients with hormonally resistant prostate cancer. J Clin Oncol. 1994 Apr;12(4):689-94. — View Citation

Oesterling JE, Hauzeur CG, Farrow GM. Small cell anaplastic carcinoma of the prostate: a clinical, pathological and immunohistological study of 27 patients. J Urol. 1992 Mar;147(3 Pt 2):804-7. — View Citation

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Papandreou CN, Daliani DD, Thall PF, Tu SM, Wang X, Reyes A, Troncoso P, Logothetis CJ. Results of a phase II study with doxorubicin, etoposide, and cisplatin in patients with fully characterized small-cell carcinoma of the prostate. J Clin Oncol. 2002 Jul 15;20(14):3072-80. — View Citation

Quoix E, Breton JL, Daniel C, Jacoulet P, Debieuvre D, Paillot N, Kessler R, Moreau L, Coëtmeur D, Lemarié E, Milleron B. Etoposide phosphate with carboplatin in the treatment of elderly patients with small-cell lung cancer: a phase II study. Ann Oncol. 2001 Jul;12(7):957-62. — View Citation

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Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore MJ, Armitage GR, Wilson JJ, Venner PM, Coppin CM, Murphy KC. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol. 1996 Jun;14(6):1756-64. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective response rate (clinical and/or biological): Clinical: objective response of target lesions according to RECIST criteria Biological: greater than 50% decrease of PSA, NSE and Chromogranin A levels		Every 6 weeks during treatment (6 cycles of carboplatin-etoposide) and 3 to 4 weeks after the end of treatment	No
Secondary	Duration of response (clinical and/or biological)		Every three months until progression	No
Secondary	Toxicity		Every 3 weeks during treatment	No
Secondary	Progression-free survival and overall survival		Every three months until progression	No