Phase III Randomized Clinical Trial of Lurbinectedin (PM01183)/Doxorubicin (DOX) versus Cyclophosphamide (CTX), Doxorubicin (DOX) and Vincristine (VCR) (CAV) or Topotecan as Treatment in Patients with Small-Cell Lung Cancer (SCLC) Who Failed One Prior Platinum-containing Line (ATLANTIS Trial).

Patients with relapsed SCLC have the worst prognosis among lung cancer
patients, with usually a life expectancy of less than six months and few
therapeutic options. New treatment options are eagerly needed, particularly
agents with novel mechanisms of action and no cross-resistance with prior
platinum-regimens.
No new treatment has been approved in Western countries over the last 15 years.
In particular, almost none of the randomized clinical trials done over the last
30 years have shown a positive outcome improvement in this setting.

PM01183 is a new chemical entity that binds the DNA leading to the formation of
DNA double strand breaks. The binding to the DNA is likely occurring in the
minor groove region and induces apoptosis and delayed progression through the
phase S/G2. PM01183 also induces the specific degradation of transcribing RNA
Pol II in several human tumor cell lines. According to a COMPARE analysis, it
does not have an overlapping mechanism of action with other 98 standard
cytotoxic agents.
Data from the cohort of 21 second-line SCLC patients treated in the Phase Ib
study with the DOX combination showed a confirmed and remarkably high activity
consistent with the synergistic effects found in vitro/in vivo, which resulted
in an ORR of 67%, with approximately 10% of CRs. This activity is
unprecedented, whereas historical data on an anthracycline-containing
combination used in a similar setting show ORRs usually in the 20-30% range.
Four patients were still ongoing treatment at the cutoff of January 2015; the
median PFS observed was 4.7 months (95%CI: 3.5-not reached). The lower boundary
of this 95%CI is in fact 3.5 months, which is usually the median PFS obtained
with the standard topotecan treatment. The preliminary results of this
uncontrolled cohort showed myelosuppression to be of potential concern in an
unselected phase III population. Thus, the DOX dose has been adapted to this
setting by a 20% reduction in addition to the G-CSF primary prophylaxis
implementation to effectively reduce the FN risk associated with the use of
this combination.
A new cohort is ongoing, and although results are not available yet, the
aforementioned promising results warrant further study in a well-designed,
prospective, larger, randomized study to better define the role of this
combination in the treatment of relapsed SCLC patients.

Primary objective:
To determine whether there is a difference in overall survival (OS) between
lurbinectedin (PM01183)/doxorubicin (DOX) and a control arm
consisting of best Investigator's choice between cyclophosphamide (CTX),
doxorubicin (DOX) and vincristine (VCR) (CAV) or topotecan, as
treatment in SCLC patients after failure of one prior platinum-containing line.

Key secondary objectives:

* Difference in OS between PM01183/DOX and CAV, in patients with CAV as best
Investigator's choice.
* OS/PFS in patients with and without baseline CNS involvement. Subgroup
analyses restricted to the sensitive and resistant populations (i.e.,
chemotherapy-free interval [CTFI] *90 days and CTFI <90 days) will also be
performed.
* PFS by an Independent Review Committee (IRC)
* Antitumor activity by IRC according to the RECIST v.1.1
* Safety profile

Multicenter, open-label, randomized, controlled phase III clinical trial to
evaluate and compare the activity and safety of an Experimental Arm consisting
of PM01183 + DOX combination followed by PM01183 alone if applicable vs. CAV or
topotecan as a control arm in SCLC patients who failed one prior
platinum-containing line.

Central randomization will be implemented; patients will be assigned to each
arm at a 1:1 ratio.
If the patient is randomized to the control arm, the assigned treatment will be
based on the reported Investigator*s preference between CAV or topotecan.
However, whenever the number of patients randomized to either CAV or topotecan
reaches 55% of the total number of patients expected in the control arm (i.e.,
165 patients), then the assigned treatment will be restricted to the remaining
option (i.e., that which has not reached 165 patients) until the end of accrual.
Stratification will be performed according to the chemotherapy-free interval
(CTFI) after first line [*180 days (very sensitive, VS) vs. 90-179 days
(sensitive; S) vs. <90 days (resistant; R)], Eastern Cooperative Oncology Group
performance status (ECOG PS) (0 vs. 1-2), baseline central nervous system (CNS)
involvement vs. no involvement, and prior immunotherapy against either
programmed cell death protein-1 (PD-1) or programmed death ligand-1 (PD-L1)
(Yes vs. No).

An Independent Review Committee (IRC) will determine the best patient response
and assign the date of objective response or progression/censoring according to
RECIST v.1.1. An Independent Data Monitoring Committee (IDMC) will oversee the
conduct of the study.

An interim safety analysis is planned after the recruitment of 150 patients
(i.e., ~75 patients into each arm). Recruitment will not be put on hold while
the interim safety analysis is being performed. The IDMC may also review
preliminary efficacy parameters (as per IA) at this time.
Crossover is not allowed.

ROUTE OF ADMINISTRATION
Experimental arm:
Doxorubicin: a short i.v. bolus/infusion over a total volume of 20 to 50 ml
dilution on 0.9% saline or 5% dextrose (as per institutional practice), via a
central or peripheral venous catheter after appropriate visual confirmation of
effective venous blood return through the line, followed by:
PM01183: i.v. infusion over one hour over a minimum of 100 ml dilution on 5%
glucose or 0.9% sodium chloride (at a fixed rate) via a central line (or a
minimum of 250 ml dilution if a peripheral line is used).

Control arm:
- Topotecan: i.v. as a 30-min infusion daily through peripheral or central
lines.
- CAV: a short i.v. infusion of CTX over a total volume of 100 to 500 ml
dilution on 0.9% saline or 5% dextrose (as per institutional practice), via a
central or peripheral venous catheter, followed by,
DOX as a short i.v. bolus/infusion over a total volume of 20 to 50 ml dilution
on 0.9% saline or 5% dextrose (as per institutional practice), via a central or
peripheral venous catheter, followed by,
VCR as a i.v. bolus over a total volume of 10 to 30 ml dilution on 0.9% saline
or 5% dextrose (as per institutional practice), via a central or peripheral
venous catheter.


STARTING DOSE AND SCHEDULE
Experimental arm:
- DOX at 40.0 mg/m2 on Day 1, immediately followed by:
- PM01183 at 2.0 mg/m2 on Day 1 q3wk (three weeks = one treatment cycle).
for a maximum of 10 cycles. Then, if applicable, DOX will be withdrawn
definitively and remaining patients will continue on maintenance until disease
progression (PD), patient refusal or unacceptable toxicity despite applicable
dose reductions, at:
- PM01183 at 3.2 mg/m2 on Day 1 q3wk. (if not more than one dose reduction
applied while on combination therapy), or:
- PM01183 at 2.6 mg/m2 on Day 1 q3wk. (if more than one dose reduction applied
while on combination therapy).

Control arm:
- Topotecan at 1.50 mg/m2 daily on Days 1-5 q3wk (three weeks = one treatment
cycle) for patients with calculated CrCL * 60 ml/min.
- Topotecan at 1.25 mg/m2 daily on Days 1-5 q3wk (three weeks = one treatment
cycle) for patients with calculated CrCL between 40 and 59 ml/min.
- Topotecan at 0.75 mg/m2 daily on Days 1-5 q3wk (three weeks = one treatment
cycle) for patients with calculated CrCL between 30 and 39 ml/min.

CAV:
- CTX at 1000 mg/m2 on Day 1, immediately followed by,
- DOX at 45.0 mg/m2 on Day 1, immediately followed by,
- VCR at 2.0 mg total flat dose on Day 1 q3wk (three weeks = one treatment
cycle).
Up to a maximum of 10 cycles. Then, if applicable, DOX will be discontinued
definitively and the remaining patients will continue on maintenance until
progressive disease, patient refusal or unacceptable toxicity despite
applicable dose reductions.

Doses in both arms, Experimental and Control, will be capped at a body surface
area (BSA) of 2.0 m2 for individuals exceeding this BSA value. Doses will have
to be recalculated for patients showing a * 10% variation from baseline in
total body weight. PM01183 total doses in mg will be rounded to the first
decimal, if necessary. DOX, CTX or topotecan total doses will be rounded, if
applicable, according to institutional guidelines/standard practice.

The patient may or may not receive any direct medical benefit from being in
this study. The illness can improve, become worse or remain the same.

Patients with relapsed SCLC have the worst prognosis among lung cancer
patients, with usually a life expectancy of less than six months and few
therapeutic options. New treatment options are eagerly needed, particularly
agents with novel mechanisms of action and no cross-resistance with prior
platinum-regimens.
No new treatment has been approved in Western countries over the last 15 years.
In particular, almost none of the randomized clinical trials done over the last
30 years have shown a positive outcome improvement in this setting.
PM01183 is a new chemical entity that induces double-strand DNA breaks through
binding to the DNA minor groove. According to a COMPARE analysis, it does not
have an overlapping mechanism of action with other 98 standard cytotoxic
agents.
The promising results in other research warrant further study in a
well-designed, prospective, larger, randomized study to better define the role
of this combination in the treatment of relapsed SCLC patients.
Considering all the data currently available for PM01183 suggests an acceptable
risk-benefit ratio. (Please refer to section J)