DNA Repair Inhibitor & Irradiation on Melanoma (DRIIM)

The recruitment status of this study is unknown because the information has not been verified recently.
Verified December 2011 by DNA Therapeutics.
Recruitment status was  Recruiting
Sponsor:
Information provided by (Responsible Party):
DNA Therapeutics
ClinicalTrials.gov Identifier:
NCT01469455
First received: October 24, 2011
Last updated: September 25, 2012
Last verified: December 2011
  Purpose

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 64 mg (approximately twice the MRSD), or higher 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 and 64 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.


Condition Intervention Phase
Local Metastatic Melanoma
Drug: DT01
Phase 1

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by DNA Therapeutics:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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


Estimated Enrollment: 25
Study Start Date: October 2011
Estimated Study Completion Date: December 2013
Estimated Primary Completion Date: September 2013 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: DT01

    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 (preferably 5 hours) prior to the radiotherapy sessions.

Detailed Description:

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 (sorafenib);
  • Immunotherapy (Ipilimumab, OncoVex, Tumor Infiltrating Lymphocytes and interleukin-2 [IL-2]);
  • Radiotherapy;
  • 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with histologically confirmed metastatic melanoma with relapsed cutaneous/subcutaneous tumors, including melanoma-in-transit, who are not eligible for immediate surgery or refractory to conventional treatment;
  • Tumor number and size: Patients with at least two tumors and/or clusters of small tumors (three is recommended) without limitation of tumor size (preferably between 0.5 cm and 3 cm in largest diameter), and not previously irradiated.

The consideration of tumor size and number can be revised based on the initial indication of efficacy, after an agreement between Principal Investigators, the DSMB and the Sponsor.

  • Normal haematopoietic function as assessed by a complete blood count including differential count.

    i. Absolute neutrophil count ≥ 1.5 x 109/L; ii. Platelet count ≥ 100 x 109/L; iii. Haemoglobin ≥ 10 g/dL (transfusions are permitted);

  • No clinically relevant abnormalities in the results of the pre-study laboratory tests:

    i. Creatinine ≤ 1.5 times UNL (upper normal of the limit) ; ii. Bilirubin ≤ 1.5 times UNL; iii. ASAT (SGOT) ≤ 2.5 times the upper limit of normal if no liver iv. metastasis and ≤ 5 times the upper limit of normal in the presence of liver metastasis ; v. ALAT (SGPT) ≤ 2.5 times the upper limit of normal if no liver metastasis and ≤ 5 times the upper limit of normal in the presence of liver metastasis; vi. Prothrombin time < 1.5 times control;

  • Age ≥18 years old;
  • The patient is willing and able to comply with the protocol for the duration of the study, including 1 day of hospitalization for PK sample at Day 1 and scheduled follow-up visits and examinations to any study related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.

Exclusion Criteria:

  • Presence of any serious concomitant systemic disorders incompatible with the study (e.g. active infection);
  • Known or suspected Central Nervous System (CNS) metastases including leptomeningeal metastases (unless the patient has been previously treated and the patient meets the three following criteria: is asymptomatic, has no evidence of active CNS metastases for more than 3 months prior to enrolment, and has no requirement for steroids or enzyme-inducing anticonvulsivants in the last 14 days);
  • Patients with a history of epilepsy;
  • Patients with a history of porphyria;
  • Patients with active psoriasis;
  • Clinically significant hepatic disease (particularly cirrhosis) or renal disease;
  • Severe gastrointestinal, neurological and blood disorders;
  • Patients receiving anti-vitamin K therapy within 10 days prior to first dose of study treatment (Low Molecular Weight Heparin (LMWH) therapy is allowed);
  • Anticancer therapy (chemotherapy, hormone therapy or immunotherapy) within 4 weeks prior to first dose of study treatment and immunotherapy with Ipilimumab, within 3 months prior to first dose of study treatment ;
  • Patients receiving cyclosporin within 10 days prior to first dose of study treatment;
  • Patients intended to receive any systemic anticancer therapy within 26 days (±2 days) from the anticipated date of the first administration of DT01 for Part I of the study; or 54 days (±2 days) from the anticipated date of the first administration of DT01 for Part II of the study;
  • Pregnant or breast-feeding women, or women of child-bearing potential unless effective methods of contraception are used. Child-bearing potential is defined as:

    i. Has experienced menarche, and ii. Has not undergone successful surgical sterilization, and iii. Is not post-menopausal (amenorrhea > 12 consecutive months or is on Hormone Replacement Therapy (HRT) with a documented plasma or serum FSH > 35 IU/L.

iv. Women using oral, implanted, injectable, mechanical or barrier products for the prevention of pregnancy, or who are practising abstinence, or where the partner is sterile (for example, a vasectomy) should be considered to be of child-bearing potential

  • Concomitant participation to another study;
  • Hypersensitivity to 4-aminoquinoline compounds (chloroquine) or to any of its derivatives;
  • HIV and Hepatitis B or C positive patients;
  • Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2
  • Retinal or visual field changes attributable to previous chloroquine administration or any other etiology;
  • Any reason why, in the Investigator's opinion, the patient should not participate in the study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01469455

Contacts
Contact: Jian Sheng Sun 0033624753239 sun@dna-therapeutics.com
Contact: Valerie Comberiati 0033 01 4083 4083 valerie.comberiati@orioncro.com

Locations
France
Hôpital Saint-André Recruiting
Bordeaux, France, 33075
Contact: Thomas Jouary, MD         
Principal Investigator: Thomas Jouary, MD         
Hôpital Ambroise Paré Recruiting
Boulogne-Billancourt, France, 92104
Contact: Philippe Saiag, MD         
Principal Investigator: Philippe Saiag, MD         
Centre Oscar Lambret Recruiting
Lille, France, 59020
Contact: Laurent Mortier, MD         
Principal Investigator: Laurent Mortier, MD         
Hôpital de la Timone Recruiting
Marseille, France, 13385
Contact: Jean Jacques Grob, MD         
Principal Investigator: Jean-Jacques Grob, MD         
Hôpital hôtel-Dieu Recruiting
Nantes, France, 44093
Contact: Brigitte Dreno, MD         
Principal Investigator: Brigitte Dreno, MD         
Groupe Hospitalier Cochin - Hôtel Dieu-Broca Recruiting
Paris, France, 75006
Contact: Marie-Françoise Avril, MD         
Principal Investigator: Marie-Françoise Avril         
Institut Curie Recruiting
Paris, France, 75248
Contact: Christophe Le Tourneau, MD         
Principal Investigator: Christophe Le Tourneau, MD, National Coordinator         
Sub-Investigator: Youlia Kirova, MD, Radiotherapist Coordinator         
Hôpital Saint-Louis Recruiting
Paris, France, 75475
Contact: Céleste Lebbé, MD         
Principal Investigator: Céleste Lebbé, MD, Dermatologist Coordinator         
Sponsors and Collaborators
DNA Therapeutics
Investigators
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 - Dermatologist Coordinator
Principal Investigator: Jean-Jacques GROB, MD Hôpital de la Timone
Principal Investigator: Brigitte DRENO, MD Hôpital hôtel-Dieu
Principal Investigator: Thomas JOUARY, MD Hôpital Saint-André
Principal Investigator: Laurent MORTIER, MD Hôpital Claude Huriez
Principal Investigator: Xavier MIRABEL, MD Centre Oscar Lambret
  More Information

No publications provided

Responsible Party: DNA Therapeutics
ClinicalTrials.gov Identifier: NCT01469455     History of Changes
Other Study ID Numbers: DT01-01
Study First Received: October 24, 2011
Last Updated: September 25, 2012
Health Authority: France: ANSM - French Health Products Safety Agency

Keywords provided by DNA Therapeutics:
Local metastatic melanoma
relapsed cutaneous/subcutaneous tumors
melanoma-in-transit

Additional relevant MeSH terms:
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas

ClinicalTrials.gov processed this record on July 09, 2014