DNA Repair Inhibitor & Irradiation on Melanoma (DRIIM)
Phase I trial will be conducted in patients suffering local metastatic melanoma with relapsed cutaneous/subcutaneous tumors including melanoma-in-transit. Based on the preclinical data package, DNA Therapeutics has considered that the risk-benefit ratio of DT01 supports the initiation of a phase I clinical study in this population. The recommended starting dose of DT01 for the first injection to human was based on NOAELs and Maximum Recommended Starting Dose (MRSD) calculations and by considering both local and systemic approaches. It was set at 16 mg (4 mg per injection site, 2 injections per tumor, 2 tumors to be treated). This starting dose will be increased up to 96 mg if no DLT occurred during dose escalation.
DT01 will be locally administered by peritumoral subcutaneous and/or intratumoral injections in combination with hypo-fractionated radiotherapy (RT) (10x 3 Gy) and chloroquine (100 mg oral QD) starting one week before DT01 and RT treatments. DT01 will be administered 3 times a week during two weeks; The study will be an open, non-randomised, multicentre, phase I dose escalation (16, 32, 48, 64 and 96 mg) safety study with a 3+3 design.
The purpose of this study will be to evaluate the safety, tolerance, pharmacokinetics of DT01 in association with palliative radiotherapy and to evaluate pharmacodynamics and the anti-tumor activity of DT01 according to RECIST criteria on day 26, 40 and 54. The duration of response (Time-To-Local Recurrence, TTLR), will be monitored 3, 6, 9 and 12 months after the beginning of the DT01 treatment.
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||An Open Label, Non-randomized, First-in-human, Multi-centre Phase I Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Locally Administered DT01 in Combination With Radiotherapy and Concomitant Dose of Chloroquine in Patients With Local Metastatic Melanoma With Relapsed Cutaneous/Subcutaneous Tumors Including Melanoma-in-transit|
- Tolerability and safety analysis, according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4 (NCI-CTCAE v4.0) criteria. [ Time Frame: over a period of 54 days ] [ Designated as safety issue: Yes ]Tolerability and safety analysis, according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4 (NCI-CTCAE v4.0) criteria.
- Profile of pharmacokinetics(PK) [ Time Frame: pre-dose,1, 2.5, 4.5, 6.5, 9,24h post dose on Day 1, and pre-dose,4.5h post dose on Day 12 ] [ Designated as safety issue: Yes ]
- Cmax The plasma peak concentration
- tmax The time to reach the peak concentration
- AUCt The area under the concentration-time curve from time zero to the last sample with the quantifiable concentration
- AUC∞ The area under the concentration-time curve from time zero to infinity
- t½ The terminal elimination half-life
|Study Start Date:||October 2011|
|Estimated Study Completion Date:||June 2015|
|Estimated Primary Completion Date:||June 2015 (Final data collection date for primary outcome measure)|
DT01 starting dose will be 16 mg and it is planned to be increased to 32, 48 mg and 64 mg, or higher.
DT01 will be administered 3 times a week (e.g., Mondays, Wednesdays and Fridays) over 2 weeks (6 administrations of DT01 in total) at least 3 hours prior to the radiotherapy sessions.
According to the WHO, the incidence of melanoma is 199,627 worldwide in 2008, of which the melanoma-in-transit is about 4%. When melanoma spreads, it does so by the lymphatic system which drains to the regional lymph nodes. Uncommonly, melanoma can become trapped in the lymphatic vessels and grow to cause tumor nodules in the skin and subcutaneous tissues between the primary site and the regional lymph node basin. These nodules are termed in-transit metastases and carry an ominous prognosis. The American Joint Committee on Cancer (AJCC) defines such in-transit metastases as any skin or subcutaneous metastases that are more than 2 cm from the primary lesion but are not beyond the regional nodal basin. The 2010 tumor node metastasis (TNM) staging system considers the melanoma-in-transit a N2c stage when they arise in the absence of nodal metastases.
The current treatment options (approved or in late stage development) are:
- Local excision, if there are only a few;
- Isolated limb perfusion (local high dose chemotherapy);
- Systemic chemotherapy (Dacarbazine, Temozolomide, Cis-platine);
- Targeted therapy (B-raf inhibitors: Vemurafenib and Dabrafenib; MEK inhibitor: Trametinib);
- Immunotherapy (Ipilimumab, Nivolumab, Pembrolizumab, OncoVEX GM-CSF, Tumor Infiltrating Lymphocytes and interleukin-2 [IL-2]);
- Photodynamic therapy;
- Laser vaporization. With rare exceptions, none of these treatments are curative. Immunotherapy results in prolongation of survival although overall response rate remains low (ref: oncovex phase II study).
According to the Sponsor's clinical development strategy and plan, the local metastatic melanoma with relapsed cutaneous/subcutaneous tumors, including melanoma-in-transit, has been chosen as the 1st indication for evaluating safety, tolerance and PK of DT01 in combination with a palliative radiotherapy (10x3 Gy). The presence of multiple cutaneous/subcutaneous tumor should provide an initial clinical evaluation of the safety and skin tolerance of the combined treatment of DT01 and 10x3 Gy irradiation, as well as a preliminary assessment of anti-tumor activity (proof of concept) of DT01 to sensitize and improve the response rate of radiotherapy (estimated about 50% response rate), and to delay local relapse.
Based on the pharmacologically active dose in human melanoma xenografted tumor in mice and the wide safety margin estimated from the toxicology data, the starting dose of 16 mg and the planned dose escalation represent a conservative approach for titration. The dose escalation will provide valuable information about the safety, tolerance and preliminary efficacy data.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01469455
|Bordeaux, France, 33075|
|Hôpital Ambroise Paré|
|Boulogne-Billancourt, France, 92104|
|Centre Oscar Lambret|
|Lille, France, 59020|
|Hôpital de la Timone|
|Marseille, France, 13385|
|Nantes, France, 44093|
|CHU de Nice - Archet 2|
|Nice, France, 06202|
|Paris, France, 75248|
|APHP Hôpital Bichat - Claude Bernard|
|Paris, France, 75877|
|Paris, France, 75475|
|Groupe Hospitalier Cochin - Hôtel Dieu-Broca|
|Paris, France, 75006|
|Centre Hospitalier Lyon Sud|
|Pierre-Bénite, France, 69495|
|Hôpital Charles Nicolle|
|Rouen, France, 76031|
|Principal Investigator:||Christophe LE TOURNEAU, MD||Institut Curie - National Coordinator|
|Principal Investigator:||Marie-Françoise AVRIL, MD||Groupe Hospitalier Cochin - Hôtel Dieu-Broca|
|Principal Investigator:||Philippe SAIAG, MD||Hôpital Européen Marseille|
|Principal Investigator:||Céleste LEBBE, MD||Hôpital Saint-Louis|
|Principal Investigator:||Jean-Jacques GROB, MD||Hôpital de la Timone|
|Principal Investigator:||Brigitte DRENO, MD||Hôpital hôtel-Dieu|
|Principal Investigator:||Caroline DUTRIAUX, MD||Hôpital Saint-André|
|Principal Investigator:||Laurent MORTIER, MD||Hôpital Claude Huriez|
|Principal Investigator:||Eve MAUBEC, MD||APHP Hôpital Bichat - Claude Bernard|
|Principal Investigator:||Luc THOMAS, MD||Centre Hospitalier Lyon Sud|
|Principal Investigator:||Jean-Philippe LACOUR, MD||CHU de Nice - Archet 2|
|Principal Investigator:||Pascal JOLY, MD||Hôpital Charles Nicolle|