Local Metastatic Melanoma Clinical Trial
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
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.
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]);
- 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.
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Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment