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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 1
18 Years
N/A
Open (Enrolling)
Both
Local Metastatic Melanoma

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Trial Information

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


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.


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.

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Tolerability and safety analysis, according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4 (NCI-CTCAE v4.0) criteria.

Outcome Description:

Tolerability and safety analysis, according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4 (NCI-CTCAE v4.0) criteria.

Outcome Time Frame:

over a period of 54 days

Safety Issue:

Yes

Principal Investigator

Christophe LE TOURNEAU, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Institut Curie - National Coordinator

Authority:

France: ANSM - French Health Products Safety Agency

Study ID:

DT01-01

NCT ID:

NCT01469455

Start Date:

October 2011

Completion Date:

December 2013

Related Keywords:

  • Local Metastatic Melanoma
  • Local metastatic melanoma
  • relapsed cutaneous/subcutaneous tumors
  • melanoma-in-transit
  • Melanoma

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