A Phase II Study Evaluating Intravenous Melphalan With Autologous Whole Blood Stem Cell Transplantation Over Three Cycles In Patients With Castration-Resistant Prostate Cancer (MEL-CAP) (MEL-CAP)

The management of (castration-resistant) prostate cancer (CRPC) is becoming increasingly complex. The use of peripheral anti-androgens with gonadorelin analogues (maximum androgen blockade) is common place. Following the failure of such an approach, several strategies may be employed. Both corticosteroids and estrogens have a role and increasingly chemotherapy is being used. The demonstration of enhanced survival using 3 weekly docetaxel has meant that this is viewed by many as the standard of care for fit patients.

Melphalan is an established alkylating drug that has demonstrated some activity in CRPC, but to date, myelosuppression has prevented adequate dosing. We have recently conducted a phase I dose escalation study using melphalan and whole blood stem cell re-infusion and it shows that median overall survival is 22 months, which is higher than the median survival rate of 19 months for Docetaxel

Data from a previous phase I study has proved the successful administration of higher doses of IV Melphalan in combination with autologous blood infusion in patients with Castration-resistant prostate cancer.

Rapid falls in circulating tumour cells were seen within 2 weeks of starting Melphalan, however slow platelet recovery meant longer periods of platelet transfusion. For this study we intend to assess the efficacy of an intensified intravenous melphalan with autologous whole blood stem cell transplantation over three treatment cycles.

39 patients will be enrolled over a 3 year period and at least 17 patients need to survive progression free at least 6-months for this study to be considered positive.

Mel-CAP is a combination chemotherapy consisting of two chemotherapy drugs:

MELPHALAN and LENOGRASTIM for 3 cycles alternately.

Study Overview

• Status: Terminated
• Conditions: Castrate Resistant Prostate Cancer
• Intervention / Treatment: Drug: Melphalan; Drug: Lenograstim

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Jonathan Shamash, MD FRCP; Phone Number: 02034657108; Email: jonathan.shamash@bartshealth.nhs.uk

Study Locations

• United Kingdom
  • London, United Kingdom, EC1A 7BE
    • St Batholowmew's Hospital NHS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Men aged ≥18 years
2. Histological diagnosis of prostate cancer

3. Progressive Castration-resistant Prostate Cancer defined as:

   • a rising PSA; or
   • development of new sites of disease in the presence of a suppressed testosterone (<1.5 nmol/l); or
   • if testosterone >1.5 nmol/l, maximum androgen blockade failure (MAB) (MAB = GnRH analogue and peripheral anti-androgen - flutamide 250 mg 3x/day or bicalutamide 50 mg/ day or cyproterone 100mg 3x/day)
4. ECOG performance status 0-2

5. Adequate haematological reserve:

   • Unsupported Hb >9.0 g/l
   • Platelets >100x109/l
   • WBC >3x109/l
   • Neutrophils >1.5x109/l

6. Renal sufficiency:

   •Creatinine <200 µmol/l

7. Hepatic sufficiency:

   • Bilirubin <30 µmol/l
   • ALT <3xULN unless due to liver metastasis
8. Able to give written informed consent and comply with the protocol study procedures

Exclusion Criteria:

1. Patients who have suffered a previous hypersensitivity reaction to melphalan
2. Patients with known hypersensitivity to lenograstim or to any of the excipients
3. History of myeloid malignancy
4. Lenograstim should not be administered concurrently with cytotoxic chemotherapy (i.e. on the same day)
5. Previous invasive carcinoma <3 years prior to study entry
6. Cardiac condition contra-indicating large volume venesection (i.e., active angina or cardiac failure)
7. Current treatment with another investigational medicinal (chemotherapeutic) product or participation in another investigational therapeutic (chemotherapy)study, at any time during the treatment period and 30 days preceding study entry.
8. Life expectancy <12 weeks
9. Unwilling or unable to provide written informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Registration.; MELCAP study has only one arm. All suitable patients will receive 3 cycles of melphalan and lenograstim alternately. Patient will start with a 3 day lenograstim (at 10mcg/kg/day) to boost up the blood cell count. Upon reaching sufficient blood cell count, patients will undergo a venesection and roughly a pint of blood is taken. After this patients will receive first cycle of Melphalan (60mg/m2). The following day patient will receive back the previously given whole blood. A treament break of 6 days between the cycles is given. After the break the patient will be given Lenograstim (10mcg/kg/day)for 6 days (until sufficient). The above regimen is repeated for cycle 2 and cycle 3 with only exception of Melphalan is given at 40mg/m2. After the cycle 3, Lenograstrim is given at 263 mcg/day for 10 days. Upon treatment completion, patients will be followed for 2 years. If the patients show disease progression, they will start hormone therapy.

Drug: Melphalan; Patients will receive Melphalan in three cycles In the first cycle they recieve 60mg/m2 and then 40mg/m2 in the next two cycles.; Drug: Lenograstim; Starting Lenograstim will be at 10mcg/kg/day and between cycles at 10mcg/kgs/day. After the third cycle patient will receive 263mcg/day for 10 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To determine the efficacy of intensified intravenous Melphalan with autologous whole blood stem cell transplantation in patients with castration resistant prostate cancer using progression free survival.	6 months progression free survival

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine weather early falls (two weeks)in circulating tumor cells (CTC)predict the progression free survival		2 weeks
To assess the changes in prostate specific antigen pre and post treament		6 months
To study progression free survival and overall survival		6 months.
To assess the effect of this schedule in reintroduction of hormone senstivity		6 months
To study the Quality of life.	QLQ-30 and PR-25 questionnaires will be collected.	6 months

Collaborators and Investigators

• Sponsor: Barts & The London NHS Trust
• Investigators: Principal Investigator: Jonathan Shamash, MD FRCP, Barts & The London NHS Trust

Publications and helpful links

General Publications

• [1] Farrugia D, Ansell W, Singh M, Philp T, Chinegwundoh F, Oliver RT. Stilboestrol plus adrenal suppression as salvage treatment for patients failing treatment with luteinizing hormone-releasing hormone analogues and orchidectomy. BJU International 2000; 8:1069-1073. [2] Nishimura K, Nonomura N, Yasunaga Y, Takaha N, Inoue H, Sugao H, Yamaguchi S, Ukimura O, Miki T, Okuyama A. Low doses of oral dexamethasone for hormone-refractory prostate carcinoma. Cancer 2000; 15:2570-6 [3] Shamash J, Dancey G, Barlow C, Wilson P, Ansell W, Oliver RTD. Chlorambucil and lomustine (CL56) in absolute hormone refractory prostate cancer: re-induction of endocrine sensitivity an unexpected finding. British Journal of Cancer (2005) 92, 36-40 [4] Melphalan and whole blood stem cell re-infusion in the management of castration-resistant prostate cancer - J Shamash, J Jacob, T Powles, S Agrawal, K Mutsvangwa, N Saunders , P Wilson and J Stebbing [ASCO 2011] [5] Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. J Clin Oncol. 2008 Jan 10;26(2):242-5. [6] A'Hern, R. P. A. 2001. 'Sample size tables for exact single-stage phase II designs.' Statistics in Medicine, Volume 20, pages 859-866. [7] Scher H.I et al (2008). Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: Recommendations of the prostrate cancer clinical trials working group. Journal of clinical oncology 26 (7): 1148-1159.

Study record dates

Study Major Dates

• Study Start: January 1, 2013
• Primary Completion (Actual): December 22, 2016
• Study Completion (Actual): December 22, 2016

Study Registration Dates

• First Submitted: July 22, 2013
• First Submitted That Met QC Criteria: July 22, 2013
• First Posted (Estimate): July 24, 2013

Study Record Updates

• Last Update Posted (Actual): April 19, 2023
• Last Update Submitted That Met QC Criteria: April 17, 2023
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Adjuvants, Immunologic; Lenograstim; Melphalan
• Other Study ID Numbers: PR 2012 06; 2012-000351-14 (EudraCT Number)