A Phase I/II Study with NAMI-A a Novel Ruthenium Anticancer Agent, and Gemcitabine Combination Second-Line Therapy in NSCLC Patients

Preclinical pharmacological studies with NAMI-A showed selective activity
against lung metastases of murine tumors (7, 8, 13, 15) and a relatively low
toxicity in mice and dogs (10, 16, 17). Preclinical toxicological studies
revealed primarily alteration of kidney, liver, and gastrointestinal function
(17).

For first-line treatment of advanced NSCLC patients with a good performance
status, the accepted standard of care is a platinum agent combined with
gemcitabine, docetaxel, paclitaxel, vinorelbine or irinotecan (19).

In a preclinical study the toxicity of NAMI-A administered in combination with
Gemcitabine was characterized. NAMI-A was administered once a week for three
weeks and Gemcitabine was administered the day after NAMI-A administration
once a week for three weeks. Both NAMI-A and Gemcitabine were admistered by
intravenous route in mouse and a dose level free of toxicity under these
conditions was established. Two dose levels of NAMI-A were evaluated (35 mg/kg
and 90 mg/kg) in combination with a single dose level of Gemcitabine (200
mg/kg). The effect of this association on body weight, haematological
parameters, clinical chemistry, absolute organ weight, relative organ weight,
organ histopathology and mortality were studied. Under these experimental
conditions, the drug combination was well tolerated at both dose levels even if
NAMI- A 35 mg/kg and Gemcitabine 200 mg/kg appeared not to be effective with
respect to histopathology analysis (20).

As NAMI-A has an important activity against lung metastases formation and
growth in different kind of induced solid tumor in mice, we may hypothesize
that the administration of NAMI-A in combination with Gemcitabine could have a
great therapeutic effect against NSCLC. This tumor has shown to have a high
rate of metastasis. NAMI-A could inhibit metastasis formation and growth. It is
very interesting that this activity was reported to be independent on both the
type of primary tumor and the stage of growth of the metastasis (7, 8, 9) in
preclinical studies. For this reason patients bearing NSCLC at late stages
could be putative to be treated with this drug association.

The primary objectives of the study are:
- to establish the optimal dose of the combination for second-line therapy with
NAMI-A and Gemcitabine (Phase I part)
- to assess the response rate according to RECIST criteria (Phase II part) in
advanced NSCLC
- to determine the profile of adverse events (both Phase I and Phase II part)

- to establish the pharmacokinetic profile of the combination of NAMI-A and
gemcitabine


The secondary objective of the study is:
- to assess the time to disease progression

The study is designed in two stages:Stage AAll eligible patients will be
treated with the combination of NAMI-A and Gemcitabine. This part of the study
aims to establish the best tolerated dose of the combination therapy. Stage
BStage B will be performed only if the combination therapy assessed in stage A
will be well tolerated. This part of the study aims to collect activity data
(response rate, time to disease progression) and further information about the
profile of adverse events.

NAMI-A will be administered at day 1, 8 and 15 while Gemcitabine will be
administered at day 2, 9 and 16, for a 28-day cycle up to progressive disease
or intolerance or patient refusal to continue therapy.
The dose levels of NAMI-A will be 300, 450, 600 and 750 mg/m2. Therapy will be
administered as an i.v. infusion over 3h.
Gemcitabine will be administered at the dose of 1000 mg/m2. Therapy will be
administered as an i.v. infusion over 30 min

The toxicity of different doses of NAMI-A was studied in a phase I clinical
trial in the Netherlands Cancer Institute (reached dose: 500 mg/m2/day) (18).
The results from this study showed that NAMI-A was in general well tolerated
when administered as an intravenous infusion over three hours for 5 days every
three weeks. Main toxicities, possibly or probably related to study
medication, were phlebitis, hypersensivity reactions and the formation of
blisters.
On the basis of this study, we aim to investigate four possible treatment
groups: NAMI-A administered at the dose of 300, 450, 600 and 750 mg/m2, once a
week for 3 weeks in a 28-days cycle up to progressive disease or intolerance or
patient refusal to continue therapy.
The safety profile of Gemcitabine is known. The risks associated with th estudy
procedures are low. For most people, needle punctures for blood samples do not
cause any serious problems. However, this procedure may cause bleeding,
bruising, discomfort, infections and or pain at the needle site.