ChemoSensMM: Comparative Study of Individualized Sensitivity-Directed Chemotherapy Versus DTIC

Sponsor

University of Wuerzburg (Other)

Overall Status

Unknown status

CT.gov ID

NCT00779714

Collaborator

Hiege-Stiftung gegen Hautkrebs (Other), medac GmbH (Industry), DCS Innovative Diagnostik Systeme (Other)

360

Enrollment

Locations

Arms

Duration (Months)

15.7

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase III trial is aimed to investigate the efficacy of an individualized, sensitivity-directed combination chemotherapy in comparison to the standard regimen DTIC.

Two question are aimed to be answered by this study:

Is the individual chemosensitivity index (BICSI) a prognostic / predictive biomarker for chemotherapy ?
Is an individualized, sensitivity-directed combination chemotherapy superior to the standard regimen DTIC in terms of survival and response ?

Condition or Disease	Intervention/Treatment	Phase
Melanoma	Drug: DTIC (dacarbazine) Drug: paclitaxel + cisplatin Drug: treosulfan + cytarabine	Phase 3

Detailed Description

Melanoma is a cutaneous neoplasm known for its high aggressiveness, its early dissemination of metastases, and its poor prognosis once metastasized. Chemotherapy with dacarbacine (DTIC) is widely accepted as the standard treatment in metastatic melanoma, with reported response rates of about 10%. This poor outcome is assumed to be due to a high chemoresistance intrinsic to melanoma cells. However, other therapeutic options like polychemotherapy, biochemotherapy, immunotherapy as well as targeted agents did not yet prove to be superior to DTIC in multicenter randomized studies.

Therefore, chemotherapy still is considered as the main therapeutic option in advanced metastatic melanoma, and a number of non-standard chemotherapeutics have been tested in small pilot studies to improve treatment efficacy. Even though complete remissions of metastatic lesions could only be observed in a few patients, these observations indicate a subgroup of patients exhibiting high sensitivity to certain anticancer drugs. An in vitro ATP-based chemosensitivity assay has been shown to differentiate between chemosensitive and chemoresistant melanoma patients. A phase-II-study testing this assay in 53 metastatic melanoma patients followed by a sensitivity-directed individualized chemotherapy demonstrated, that the chemosensitivity profile of an individual patient, reflected by the best individual chemosensitivity index (BICSI), correlated with therapy outcome in terms of therapy response and patient overall survival (Ugurel S: Clin Cancer Res 2006). Interestingly, a surprisingly high proportion of about 2/5 of the investigated patient cohort were classified as chemosensitive, the remaining 3/5 were classified as chemoresistant. Objective response was 36.4% in chemosensitive patients compared to 16.1% in chemoresistant patients (p=0.114); progression arrest (CR+PR+SD) was 59.1% versus 22.6% (p=0.01). Chemosensitive patients showed an increased overall survival of 14.6 months compared to 7.4 months in chemoresistant patients (p=0.041).

These encouraging results prompted the initiation of this randomized phase-III-trial investigating an individualized sensitivity-directed combination chemotherapy compared to the current standard treatment DTIC, as first-line treatment in metastatic melanoma. The therapeutics for chemosensitivity testing and treatment of patients were chosen considering the results of the phase-II-trial (paclitaxel+cisplatinum, treosulfan+cytarabine).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

360 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Prospectively Randomized Phase III Study of an Individualized Sensitivity-Directed Combination Chemotherapy Versus DTIC as First-Line Treatment in Stage IV Metastatic Melanoma

Study Start Date :

Oct 1, 2008

Anticipated Primary Completion Date :

Oct 1, 2012

Anticipated Study Completion Date :

Apr 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A (individualized combined chemotherapy)	Drug: paclitaxel + cisplatin paclitaxel 200 mg/m2 cisplatin 50 mg/m2 d1 every 21 days Other Names: taxomedac + cisplatin medac Drug: treosulfan + cytarabine treosulfan 2500 mg/m2, d2 cytarabine 100 mg/m2, d1-3 every 21 days Other Names: ovastat + alexan
Active Comparator: B (DTIC monochemotherapy)	Drug: DTIC (dacarbazine) 1000 mg/m2, d1 every 21 days Other Names: detimedac

Arm

Intervention/Treatment

Experimental: A (individualized combined chemotherapy)

Drug: paclitaxel + cisplatin

paclitaxel 200 mg/m2 cisplatin 50 mg/m2 d1 every 21 days

Other Names:

taxomedac + cisplatin medac

Drug: treosulfan + cytarabine

treosulfan 2500 mg/m2, d2 cytarabine 100 mg/m2, d1-3 every 21 days

Other Names:

ovastat + alexan

Active Comparator: B (DTIC monochemotherapy)

Drug: DTIC (dacarbazine)

1000 mg/m2, d1 every 21 days

Other Names:

detimedac

Outcome Measures

Primary Outcome Measures

Disease-specific overall survival [4 years]

Secondary Outcome Measures

Objective response [4 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically confirmed melanoma of the skin, mucosa, or unknown primary, diagnosed with surgically unresectable distant metastases (stage IV according to AJCC).
At least one measurable target lesion according to RECIST, assessed by CT or MRI (tumor assessment by X-ray or ultrasonography only is not allowed).
Access to a biopsy of ~1 cm3 from at least one metastatic lesion for in vitro chemosensitivity testing. Cell suspensions from malignant effusions are also eligible.
No prior chemotherapy in stage IV (adjuvant chemotherapy in stage III allowed; one prior regimen of immunotherapy or targeted therapy in stage IV allowed).
No evidence of brain/CNS metastases. Former history of brain/CNS metastases, which have been treated successfully, and are no longer visible in CT/MRI is allowed.
Last complete tumor assessment (CT or MRI of thorax, abdomen and brain) not older than 14 days prior to registration, and not older than 5 weeks prior to onset of study treatment.
ECOG/WHO performance index of 0 or 1.
Patients must have stopped any kind of previous antineoplastic therapy for at least 2 weeks prior to registration, and at least 4 weeks prior to treatment onset.
Patients must not have concurrent or recent malignancies except for surgically cured carcinoma in-situ of the cervix and basal or squamous cell carcinoma of the skin. Patients with previous malignancies, which have been treated with a subsequent disease-free interval of at least 5 years, are eligible.
Patient age ≥ 18 years.
Adequate hematological, renal and liver function as defined by the following laboratory values performed within 14 days prior to randomisation:
absolute neutrophil count (ANC) ≥ 1.5 x 109/l
platelet count ≥ 100 x 109/l
hemoglobin ≥ 9 g/dl
urea and serum creatinine ≤ 2 times upper normal limit (UNL)
total and direct serum bilirubin ≤ 2 times UNL
GOT or GPT ≤ 2.5 times UNL; ≤ 5 times UNL is allowed in case of liver metastasis
alkaline phosphatase < 2.5 times UNL
Female patients should not be pregnant or nursing. Women of childbearing potential should be using a highly effective method of birth control (e.g. implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence or vasectomised partner). For subjects using a hormonal contraceptive method, information regarding the product under evaluation and its potential effect on the contraceptive should be addressed.
Male patients should use an effective method of contraception.
Before registration, written informed consent must be given according to GCP guidelines and national/local regulations. Patients must be willing and giving informed consent to participation in the trial.

Exclusion Criteria:

All metastatic lesions are surgically resectable.
Prior chemotherapy in stage IV (adjuvant chemotherapy in stage III allowed; one prior regimen of immunotherapy or targeted therapy in stage IV allowed).
Primary melanoma of the uvea / choroidea.
Evidence of brain/CNS metastases. Former history of brain/CNS metastases, which have been treated successfully, and are no longer visible in CT/MRI is allowed.
ECOG/WHO performance index of 2 or higher
Concurrent or recent malignancies except for surgically cured carcinoma in-situ of the cervix and basal or squamous cell carcinoma of the skin. Patients with previous malignancies, which have been treated with a subsequent disease-free interval of at least 5 years, are eligible.
Any severe or uncontrolled hematological, renal or liver dysfunction as defined by the laboratory values given in Inclusion Criteria.
Any clinically uncontrolled infectious disease including HIV positivity or AIDS-related illness.
Any female patients who are pregnant or nursing.
Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration for the trial.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Dept of Dermatology, University of Aachen	Aachen	Germany	52074
2	Dept of Dermatology, University of Berlin Charite	Berlin	Germany	10117
3	Dept of Dermatology, University of Bochum	Bochum	Germany	44791
4	Medizinisches Zentrum Bonn Friedensplatz	Bonn	Germany	53111
5	Dept of Dermatology, University of Essen	Essen	Germany	45147
6	Dept of Dermatology, University of Frankfurt	Frankfurt / Main	Germany	60590
7	Dermatology, Klinikum Frankfurt/Oder	Frankfurt/Oder	Germany	15236
8	Dept of Dermatology, University of Hannover	Hannover	Germany	30449
9	Dept of Dermatology, Saarland University	Homburg/Saar	Germany	66421
10	Dept of Dermatology, University of Jena	Jena	Germany	07740
11	Dept of Dermatology, University of Schleswig-Holstein Campus Kiel	Kiel	Germany	24105
12	Dermatology, Klinikum Ludwishafen	Ludwigshafen	Germany	67063
13	Dept of Dermatology, University of Schleswig-Holstein Campus Luebeck	Luebeck	Germany	23538
14	Dept of Dermatology, Univeristy of Magdeburg	Magdeburg	Germany	39120
15	Dept of Dermatology, University of Mainz	Mainz	Germany	55131
16	Dept of Dermatology, University of Mannheim	Mannheim	Germany	68167
17	Dept of Dermatology, University of Marburg	Marburg	Germany	35033
18	Dept of Dermatology, University of Muenchen	Muenchen	Germany	80337
19	Dept of Dermatology, University of Muenster	Muenster	Germany	48149
20	Dept of Medical Oncology, Fachklinik Hornheide	Muenster	Germany	48157
21	Dermatology, Klinikum Dorothea Christiane Erxleben	Quedlinburg	Germany	06484
22	Dept of Dermatology, University of Tuebingen	Tuebingen	Germany	72086
23	Dept of Dermatology, University of Wuerzburg	Wuerzburg	Germany	97080