Antitumor activity of lurbinectedin (PM01183) and doxorubicin in relapsed small-cell lung cancer: Results from a phase I study

Abstract

Background:
Lurbinectedin (PM01183) has synergistic antitumor activity when combined with doxorubicin in mice with xenografted tumors. This phase I trial determined the recommended dose (RD) of doxorubicin (bolus) and PM01183 (1-h intravenous infusion) on day 1 every 3 weeks (q3wk), and obtained preliminary evidence of antitumor activity for this combination in small-cell lung cancer (SCLC).

Patients and methods:
Patients with advanced solid tumors received doxorubicin and PM01183 following a standard dose escalation design and expansion at the RD. Twenty-seven patients had relapsed SCLC: 12 with sensitive disease (platinum-free interval ≥90 days) and 15 with resistant disease (platinum-free interval <90 days).

Results:
Doxorubicin 50 mg/m2 and PM01183 4.0 mg flat dose was the RD. In relapsed SCLC, treatment tolerance at the RD was manageable. Transient and reversible myelosuppression (including neutropenia, thrombocytopenia, and febrile neutropenia) was the main toxicity, managed with dose adjustment and colony-stimulating factors. Fatigue (79%), nausea/vomiting (58%), decreased appetite (53%), mucositis (53%), alopecia (42%), diarrhea/constipation (42%), and asymptomatic creatinine (68%) and transaminase increases (alanine aminotransferase 42%; aspartate aminotransferase 32%) were common, and mostly mild or moderate. Complete (n = 2, 8%) and partial response (n = 13, 50%) occurred in relapsed SCLC, mostly at the RD. Response rates at second line were 91.7% in sensitive disease [median progression-free survival (PFS)=5.8 months] and 33.3% in resistant disease (median PFS = 3.5 months). At third line, response rate was 20.0% (median PFS = 1.2 months), all in resistant disease.

Conclusion:
Doxorubicin 50 mg/m2 and PM01183 4.0 mg flat dose on day 1 q3wk has shown remarkable activity, mainly in second line, with manageable tolerance in relapsed SCLC, leading to further evaluation of this combination within an ongoing phase III trial.

Full text

ORIGINAL ARTICLE
Antitumor activity of lurbinectedin (PM01183) and
doxorubicin in relapsed small-cell lung cancer:
results from a phase I study
E. Calvo
1
, V. Moreno
2
, M. Flynn
3
, E. Holgado
1
, M. E. Olmedo
4
, M. P. Lopez Criado
5
, C. Kahatt
6
,
J. A. Lopez-Vilari~
no
6
, M. Siguero
6
, C. Fernandez-Teruel
6
, M. Cullell-Young
6
, A. Soto Matos-Pita
6
&
M. Forster
3
*
1
START Madrid – Oncology, HM CIOCC, Hospital Madrid Norte Sanchinarro, Madrid;
2
START Madrid – Oncology, FJD (Hospital Fundaci
on Jime´nez D

ıaz), Madrid,
Spain;
3
Department of Oncology, University College of London Hospital and UCL Cancer Institute, London, UK;
4
Department of Oncology, Hospital Ramon y Cajal,
Madrid;
5
Department of Oncology, M.D. Anderson Cancer Center, Madrid;
6
Clinical R&D, Pharma Mar, S.A., Colmenar Viejo, Madrid, Spain
*Correspondence to: Dr Martin Forster, Department of Oncology, University College of London Hospital, 235 Euston Road, London NW1 2BU, UK. Tel: þ44-020-3447-5085;
Fax: þ44-020-3447-9055; E-mail: m.forster@ucl.ac.uk
Background: Lurbinectedin (PM01183) has synergistic antitumor activity when combined with doxorubicin in mice with
xenografted tumors. This phase I trial determined the recommended dose (RD) of doxorubicin (bolus) and PM01183 (1-h
intravenous infusion) on day 1 every 3 weeks (q3wk), and obtained preliminary evidence of antitumor activity for this
combination in small-cell lung cancer (SCLC).
Patients and methods: Patients with advanced solid tumors received doxorubicin and PM01183 following a standard dose
escalation design and expansion at the RD. Twenty-seven patients had relapsed SCLC: 12 with sensitive disease (platinum-free
interval 90 days) and 15 with resistant disease (platinum-free interval <90 days).
Results: Doxorubicin 50 mg/m
2
and PM01183 4.0mg flat dose was the RD. In relapsed SCLC, treatment tolerance at the RD was
manageable. Transient and reversible myelosuppression (including neutropenia, thrombocytopenia, and febrile neutropenia)
was the main toxicity, managed with dose adjustment and colony-stimulating factors. Fatigue (79%), nausea/vomiting (58%),
decreased appetite (53%), mucositis (53%), alopecia (42%), diarrhea/constipation (42%), and asymptomatic creatinine (68%) and
transaminase increases (alanine aminotransferase 42%; aspartate aminotransferase 32%) were common, and mostly mild or
moderate. Complete (n¼2, 8%) and partial response (n¼13, 50%) occurred in relapsed SCLC, mostly at the RD. Response rates
at second line were 91.7% in sensitive disease [median progression-free survival (PFS)¼5.8 months] and 33.3% in resistant
disease (median PFS ¼3.5 months). At third line, response rate was 20.0% (median PFS ¼1.2 months), all in resistant disease.
Conclusion: Doxorubicin 50 mg/m
2
and PM01183 4.0 mg flat dose on day 1 q3wk has shown remarkable activity, mainly in
second line, with manageable tolerance in relapsed SCLC, leading to further evaluation of this combination within an ongoing
phase III trial.
Key words:lurbinectedin, PM01183, small-cell lung cancer, phase I study
Introduction
The synthetic tetrahydroisoquinoline lurbinectedin (PM01183;
Pharma Mar S.A., Colmenar Viejo, Madrid, Spain) has broad
in vitro activity in the low nanomolar range [1]. PM01183 inhibits
active transcription in tumor cells through binding to CG-rich
sequences, irreversible stalling and degradation of elongating RNA
polymerase II on the DNA template, generation of XPF-dependent
single- and double-strand DNA breaks, and subsequent apoptosis
[2]. PM01183 also has a selective apoptotic-inducing effect on
mononuclear phagocytes, and inhibits the production of inflamma-
tory cytokines by these cells [3].
A study in mice bearing xenografted human tumors found
strong dose-dependent antitumor activity for the combination of
V
CThe Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use,
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Annals of Oncology 28: 2559–2566, 2017
doi:10.1093/annonc/mdx357
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PM01183 and doxorubicin, with a synergistic combination index
1. Doxorubicin has a different mechanism of action and its clin-
ical toxicity profile does not completely overlap that of PM01183
[4]. A prior phase I trial found antitumor activity for single-agent
PM01183 in patients with advanced solid tumors [5].
Based on these findings, this phase I trial was designed to deter-
mine the recommended dose (RD), and evaluate the safety and
antitumor activity of doxorubicin combined with PM01183 ad-
ministered every three weeks (q3wk) in selected advanced solid
tumors. Tumor types for this study were selected based on pre-
clinical evidence of potential activity of PM01183 and on the
standard clinical use of doxorubicin in solid tumor patients. Of
note, small-cell lung cancer (SCLC) cells are addicted to lineage-
specific and proto-oncogenic transcription factors that support
cell growth, hence further suggesting that PM01183 could play a
role in the treatment of this tumor type. Due to the relevance of
the antitumor activity observed during escalation, the results
shown here are focused on relapsed SCLC patients.
Materials and methods
Patients were recruited in Spain and the UK. The study followed ICH
Good Clinical Practice guidelines, and was approved by the respective
Research Ethics Committees. Written informed consent was obtained
from all patients before study-specific procedures. The study is registered
at http://www.clinicaltrials.gov as NCT01970540.
Eligibility criteria
Eligible patients were aged 18–75 years with confirmed advanced solid
tumors pre-treated with 1–2 cytotoxic-containing chemotherapy regimens
for advanced disease (not anthracyclines); who had recovered from previous
toxicities; 3 weeks since last anticancer therapy and 6weeks since sys-
temic nitrosoureas and mitomycin C; life expectancy 3 months; Eastern
Cooperative Oncology Group performance status 1; normal left ventricu-
lar ejection fraction (LVEF); and adequate bone marrow, hepatic and renal
function.
Patients were excluded if they had symptomatic progressive or
corticosteroid-requiring brain metastases or leptomeningeal involve-
ment; were pregnant or lactating women, or not using effective contra-
ception; had prior radiation therapy (>35% of bone marrow), prior
bone marrow/stem cell transplantation, relevant cardiac disease, alcohol
consumption or cirrhosis, active uncontrolled infection, or any disease
interfering with study outcome.
Study treatment
Treatment consisted of a fixed dose of doxorubicin 50mg/m
2
as bolus fol-
lowed by escalating doses of PM01183 intravenously (i.v.) over 1 h on day
1 q3wk. Doxorubicin was administered to a maximum cumulative dose of
450 mg/m
2
. After reaching this, patients were switched to PM01183 alone
at its single-agent RD of 7.0 mg flat dose (FD) on day 1 q3wk to prevent
doxorubicin-induced cardiomyopathy [6]. Commercially available doxo-
rubicin was provided. PM01183 was supplied as a lyophilized powder con-
centrate, reconstituted in sterile water for injection, and diluted with
glucose 5% or sodium chloride 0.9% solution. All patients received stand-
ard antiemetic prophylaxis before each infusion. Treatment was given until
disease progression, unacceptable toxicity, intercurrent illness precluding
study continuation, patient refusal and/or non-compliance with study re-
quirements, treatment delay >15 days (except if clear clinical benefit), and
requirement of >2dosereductions.
Dose escalation
Dose escalation followed a standard 3 þ3 design. Doxorubicin dose was
standard for combination schedules. The starting PM01183 dose (3.5 mg
FD daily) was 50% the RD defined for PM01183 alone on day 1 q3wk [5].
Dose-limiting toxicities were evaluated during cycle 1 and comprised
grade 4 neutropenia >7 days, grade 3 febrile neutropenia, grade 4
thrombocytopenia (or grade 3 requiring transfusion), grade 4 transamin-
ase increase (or grade 3 >14 days), grade 3 creatinine phosphokinase
increase, and clinically relevant grade 3 non-hematological toxicities.
Study assessments
Hematology and biochemistry tests were done at baseline, weekly during
cycle 1, and before each PM01183 infusion and on day 10 during subse-
quent cycles. Electrocardiograms and LVEF assessments were done at
baseline and repeated at doxorubicin discontinuation or if clinically
indicated.
Antitumor activity was evaluated every two cycles according to the
Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1 [7]. Overall
response rate (ORR) was the percentage of patients with complete (CR) or
partial response (PR), and disease control rate (DCR) was the percentage
of patients with response or stable disease (SD). Time-to-event parameters
were progression-free survival (PFS) and duration of response.
Adverse events (AEs) and laboratory abnormalities were graded with
the National Cancer Institute Common Terminology Criteria for
Adverse Events (NCI-CTCAE) v.4 [8] and coded using the Medical
Dictionary for Regulatory Activities (MedDRA) v.14.1.
Statistical analysis
Continuous variables were presented with summary statistics and cat-
egorical variables in frequency tables. Time-to-event variables were calcu-
lated using Kaplan–Meier approach. Binomial exact distribution was
used to calculate 95% confidence intervals (95% CIs) for categorical
variables.
Results
Dose escalation
Seventy-four patients were included during dose escalation. Most
common tumor types were SCLC (n¼28, 38%), endometrial can-
cer (n¼15, 20%), neuroendocrine tumors (n¼9, 12%) and soft
tissue sarcoma (n¼8, 11%). Four dose levels were evaluated.Most
DLTs were hematological and mostly occurred at the highest dose
level (doxorubicin 50 mg/m
2
and PM01183 5.0 mg FD), which was
defined as the maximum tolerated dose. The RD was determined
at doxorubicin 50 mg/m
2
and PM01183 4.0 mg FD [9].
Characteristics of SCLC patients and treatment
All 28 SCLC patients were treated with doxorubicin/PM01183,
and 27 of them were included in the present analysis (Table 1);
one patient was considered not evaluable because he had lepto-
meningeal carcinomatosis in cycle 1 that had not been evaluated
at baseline. Median age was 62 years (range, 48–73 years) and
many were male (n¼17, 63%). At baseline, 18 (67%) had bulky
disease (target lesion >50 mm), 6 (22%) had brain metastases,
and 13 (48%) had received prophylactic cranial irradiation.
Twelve patients (44%) had sensitive disease [defined as
platinum-free interval (PFI) 90 days] and received doxorubicin/
PM01183 as second-line therapy. The other 15 (56%) had resistant
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disease (defined as PFI <90 days) and received it as second line
(n¼9), third line (n¼5) or fourth line (n¼1).
Six patients were treated below the RD, 19 at the RD (doxorubi-
cin 50 mg/m
2
þPM011834.0 mg FD), and 2 above the RD. A total
of 126 cycles of doxorubicin/PM01183 were administered at all
dose levels (101 cycles at the RD). Median relative dose intensity at
the RD was 95.8% (range, 78.6%–103.1%) for doxorubicin, and
94.5% (range, 70.1%–101.2%) for PM01183. Eight patients
(29.6%) received 45 cycles of single-agent PM01183 after doxo-
rubicin discontinuation [median relative dose intensity¼87.4%
(range, 76.5%–100.0%), including seven patients previously
treated with the combination at the RD]. Total median of cycles
(combination and single-agent PM01183) per patient was 4 (range,
1–33 cycles) at all dose levels and 6 (range, 1–33 cycles) at the RD.
Table 1. Baseline characteristics of patients with relapsed SCLC
Doxorubicin1PM01183
Second line Third or fourth line
a
Sensitive (n512) Resistant (n59) Resistant (n56)
n%n%n%
Gender
Male 10 83 6 67 1 17
Female 2 17 3 33 5 83
Median age (range) (years) 62.5 (48–73) 62.0 (50–70) 58.5 (50–63)
ECOG performance status
0 8 67 1 11 3 50
1 4 33 8 89 3 50
Median BSA (range) (m
2
) 1.9 (1.3–2.0) 1.9 (1.7–2.3) 1.7 (1.5–1.8)
Median albumin (range) (g/dl) 4.1 (3.2–4.8) 4.2 (2.5–4.5) 4.0 (3.6–4.5)
Median hemoglobin (range) (g/dl) 13.5 (10.5–15.2) 12.1 (9.2–17.7) 11.6 (9.6–13.2)
Median LDH (range) (x ULN) 0.6 (0.3–1.6) 1.1 (0.5–3.4) 1.7 (0.7–2.8)
Smoker
Current 2 17 4 44 2 33
Former
b
10 83 5 56 4 67
Median number of sites of disease involvement (range) 2.5 (1–4) 3 (1–5) 2.5 (2–7)
Metastasis at baseline
Visceral 6 50 8 89 3 50
Liver 6 50 3 33 2 33
Bone 3 25 4 44 2 33
CNS – – 4 44 2 33
Bulky disease (any target lesion >50 mm) 5 42 8 89 5 83
PCI 10 83 1 11 2 33
Prior therapy
Platinum compound 12 100 9 100 6 100
Etoposide 12 100 9 100 6 100
Topotecan – – – – 3 50
Irinotecan – – – – 2 33
Other (investigational drugs) 1
c
81
d
11 – –
PFI
e
<90 days – – 9 100 6 100
90–179 days 7 58 – – – –
180 days 5 42 – – – –
TTP to prior therapy (months) 7.7 (2.1–13.6) 4.5 (1.2–6.0) 3.3 (1.6–6.4)
a
Only one patient with resistant disease received the combination as fourth-line therapy.
b
Defined as an adult patient who used to smoke but who had quit smoking by the time of registration into this trial.
c
LY2940680.
d
Nivolumab.
e
Time from the last prior platinum therapy before inclusion in the study.
BSA, body surface area; CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; PCI, prophylactic cranial
irradiation; PFI, platinum-free interval; SCLC, small-cell lung cancer; TTP, time to progression; ULN, upper limit of normal.
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Efficacy
Twenty-six patients were evaluable for efficacy. Overall, ORR was
57.7% (95% CI, 36.9%–76.6%) and DCR was 69.2% (95% CI,
48.2%–85.6%) (Table 2).
As second line, 14 of 21 patients (ORR ¼66.7%; 95% CI,
43.0%–85.4%) had response. ORR was 91.7% (95% CI, 61.5%–
99.8%) in sensitive disease [two CRs (16.7%) and nine PRs
(75.0%) among 12 patients], and 33.3% (95% CI, 7.5%–70.1%)
in resistant disease (three PRs among nine patients). Most re-
sponses were confirmed (14 of 15). One patient with sensitive dis-
ease and two with resistant disease had SD; DCR was 100.0%
(95% CI, 73.5%–100.0%) in sensitive disease and 55.6% (95%
CI, 21.2%–86.3%) in resistant disease (Table 2).
As third line (all resistant disease), ORR/DCR was 20.0% (95%
CI, 0.5%–71.6%) (one PR among five patients) (Table 2).
Tumor shrinkage occurred in 20 of 26 patients (77%) (Figure
1): all 12 with sensitive disease, and 7 of 9 (78%) with resistant
disease as second line; and 1 of 5 (20%) with resistant disease as
third line. Target lesion size decrease was maintained in seven of
eight (88%) patients treated with single-agent PM01183.
Median PFS was 4.1 months (95% CI, 1.4–5.8 months) in all
patients: 4.7 months (95% CI, 3.5–8.4 months) as second line
[sensitive disease: 5.8 months (95% CI, 3.6–10.9 months); resist-
ant disease: 3.5 months (95% CI, 1.1–8.0 months)], and
1.2 months (95% CI, 0.6–4.1 months) as third line (Figure 2).
Seven patients achieved PFS >6 months (Figure 1), including one
with sensitive disease who received 33 cycles as second line and
had CR and a PFS of 23.6 months before discontinuing due to
disease progression (time-to-progression after first-line therapy
had been 2.1 months).
Median duration of response was 4.5 months (95% CI, 2.3–
7.8 months) in all patients and as second line [sensitive disease:
4.5 months (95% CI, 2.1–9.1 months); resistant disease: 6.7 months
(95% CI, 2.3–7.2 months)]; and 2.8 months in one patient as third
line.
Twelve responses (including both CRs) occurred at the RD.
ORR was 64.7% (95% CI, 38.3%–85.7%) as second line [sensitive
disease: 88.9% (95% CI, 51.7%–99.7%); resistant disease: 37.5%
(95% CI, 8.5%–75.5%)]; and 50.0% (95% CI, 1.2%–98.7%) as
third line. Median PFS was 4.1 months (95% CI, 1.4–9.0 months)
as second line [sensitive disease: 9.0 months (95% CI, 3.3–
11.7 months); resistant disease: 2.4 months (95% CI, 1.1–
8.0 months)]; and 2.4 months (95% CI, 0.6–4.1 months) as third
line. Median duration of response was 6.7 months (95% CI, 2.1–
9.1 months) as second line [sensitive disease: 5.6 months (95%
CI, 1.0–9.8 months); resistant disease: 6.7 months (95% CI, 2.3–
7.2 months)].
Six patients at all dose levels had brain metastases at baseline
that were considered non-target lesions for the evaluation of the
disease. Of these six patients, four received the doxorubicin/
PM01183 combination as second-line therapy and two as third-
line therapy. All six patients discontinued treatment due to dis-
ease progression. In three of these patients, disease progression
consisted of the appearance of new tumor lesions after two to six
cycles while the brain lesions at baseline remained apparently sta-
ble (n¼2) or were not evaluated again while on treatment
(n¼1). Two patients showed progression in baseline brain le-
sions after two and five cycles. Finally, one patient had clinical de-
terioration after three cycles while the baseline brain lesions
remained apparently stable.
Toxicity
All patients were evaluable for safety. At the RD, the most com-
mon combination-related non-hematological AEs were fatigue
(n¼15; 79%), nausea/vomiting (n¼11; 58%), decreased
Table 2. Best tumor response according to Response Evaluation Criteria In Solid Tumors (RECIST)
Doxorubicin 1PM01183 Total (n526)
a
Second line Third line
Sensitive (n512) Resistant (n59) Resistant (n55)
n%n%n%n%
CR 2 16.7 – – – – 2 7.7
PR 9
b
75.0 3 33.3 1 20.0 13 50.0
SD 1 8.3 2 22.2 – – 3 11.5
PD – – 4 44.4 4 80.0 8 30.8
ORR (95% CI) 91.7% (61.5%–99.8%) 33.3% (7.5%–70.1%) 20.0% (–) 57.7% (36.9%–76.6%)
DCR (95% CI) 100.0% (73.5%–100.0%) 55.6% (21.2%–86.3%) 20.0% (–) 69.2% (48.2%–85.6%)
Median duration of response
(months) (95% CI)
4.5 (2.1–9.1) 6.7 (2.3–7.2) 2.8 (–) 4.5 (2.3–7.8)
a
One patient, who was the only one in this study who received the combination as fourth-line therapy, was not evaluable for efficacy and has been
excluded.
b
Partial response could not be confirmed in one patient.
CI, confidence interval; CR, complete response; DCR, disease control rate; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable
disease.
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100
80
60
40
20
1.2 1.2 1.2 1.2 1.4
0.6 1.1 3.8
1.2
9.6
4.8
3.5 3.3 4.1
8.0
5.8
4.13.6
10.9
8.4 9.0 11.7
23.6
4.6
2.7
4.7*
**
*****
–20
–40
–60
–80
0
3
6
9
12
15
Progression free survival (months)
18
21
24
27
– 100
2nd/R
2nd/R
2nd/R
2nd/R
2nd/R
2nd/R
2nd/R
3rd/R
2nd/R
2nd/R
2nd/R
2nd/S
2nd/S
2nd/S
2nd/S
2nd/S
2nd/S
2nd/S
2nd/S
2nd/S
2nd/S
2nd/S
2nd/S
2nd/S
3rd/R
3rd/R
3rd/R
3rd/R
3rd/R
0RD
RD RD RD RD RD
RD
RD RD RD RD <RD <RD RD RD RD RD RD RD RD RD
<RD<RD <RD
100
80
60
40
20
Chan
g
e from baseline (%)
–20
–40
–60
–80
– 100
CR
PR
SD
PD
0
<RD
>RD
Figure 1. Waterfall plot showing maximum variation of target lesions and progression-free survival in patients with at least one radiological
tumor assessment (n¼26). Sixteen patients had target lesion decrease >30%: 15 with CR or PR, and 1 with PD who had response in extracra-
nial lesions and disease progression in the brain. Red stars ¼treatment switch to PM01183 alone. 2nd/R, second-line therapy and resistant
disease; 2nd/S, second-line therapy and sensitive disease; 3rd/R, third-line therapy and resistant disease; CR, complete response; PD, progres-
sive disease; PR, partial response; SD, stable disease.
1.0
0.9
0.8
2nd/S
2nd/R
3rd/R
0.7
0.6
0.5
0.4
Cumulative probability
0.3
0.2
0.1
0.0
036912
Time (months)
Global (N=26 C=1) Median PFS: 4.1 months (95%CI: 1.4-5.8)
2nd/S (N=12 C=1) Median PFS: 5.8 months (95%CI: 3.6-10.9)
2nd/R (N=9 C=0) Median PFS: 3.5 months (95%CI: 1.1-8.0)
Censored
3rd/R (N=5 C=0) Median PFS: 1.2 months (95%CI: 0.6-4.1)
15 18 21 24
Figure 2. Kaplan–Meier plot of progression-free survival with doxorubicin/PM01183. 2nd/R, second-line therapy and resistant disease; 2nd/S, second-
line therapy and sensitive disease; 3rd/R, third-line therapy and resistant disease; C, censored; CI, confidence interval; PFS, progression-free survival.
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appetite, mucositis (n¼10 each; 53%), alopecia and diarrhea/con-
stipation (n¼8 each; 42%) (Table 3). Most AEs were grade 1/2.
Grade 3 related AEs comprised febrile neutropenia, fatigue,
mucositis and pneumonia. The only related grade 4 AE was one fe-
brile neutropenia episode. Regardless of relationship, hematolo-
gical abnormalities were common and severe cases comprised
neutropenia (n¼18; 95%) [grade 4 lasting a median of 4 days
(range, 2–13 days)], leukopenia (n¼15; 79%), anemia (n¼9;
47%), and thrombocytopenia (n¼5; 26%) (Table 3). Most bio-
chemical abnormalities were grade 1/2; the most frequent were
creatinine (n¼13; 68%), alanine aminotransferase (n¼8; 42%)
and aspartate aminotransferase (n¼6; 32%) increases. Grade 3
increases in transaminases and bilirubin occurred in one patient
and were concomitant with bile duct obstruction unrelated to
treatment.
At the RD, nine patients required red blood cell transfusions,
one had platelets transfusions, and seven required granulocyte
colony-stimulating factor support. Treatment-related AEs re-
sulted in 12 delays, two dose reductions, and one discontinu-
ation. No toxic deaths occurred.
Most common AEs related to single-agent PM01183 were fa-
tigue (all eight patients), decreased appetite (n¼4; 50%) and alo-
pecia (n¼3; 38%). Most were grade 1/2; single episodes of grade
3 febrile neutropenia, grade 3 hypomagnesemia, and grade 4
Table 3. Treatment-related adverse events and laboratory abnormalities regardless of relationship at the RD (10%of patients or grade 3/4)
Doxorubicin 50.0 mg/m
2
1PM01183 4.0 mg FD (n519)
NCI-CTCAE grade
3 4 All
n%n%n%
Treatment-related AEs
Alopecia – – – – 8 42
Conjunctivitis – – – – 2 11
Decreased appetite – – – – 10 53
Diarrhea/constipation – – – – 8 42
Dizziness – – – – 2 11
Dry mouth – – – – 2 11
Dry skin – – – – 2 11
Dysgeusia – – – – 7 37
Esophageal candidiasis 1 5 – – 1 5
Fatigue 2 11 – – 15 79
Hypokalemia 1 5 – – 1 5
Hypomagnesemia 1 5 – – 1 5
Mucositis 2 11 – – 10 53
Myalgia – – – – 3 16
Nail disorder – – – – 2 11
Nausea/vomiting – – – – 11 58
Neutropenic infection 1 5 – – 1 5
Pneumonia 2 11 – – 2 11
Pyrexia – – – – 2 11
Somnolence – – – – 2 11
Hematological abnormalities
Anemia 9 47 – – 18 95
Febrile neutropenia 4 21 1 5 5 26
Leukopenia 9 47 6 32 19 100
Neutropenia 3 16 15 79 19 100
Thrombocytopenia 2 11 3 16 17 90
Biochemical abnormalities
ALP increased – – – – 5 26
ALT increased 1 5 – – 8 42
AST increased 1 5 – – 6 32
Bilirubin increased 1 5 – – 5 26
Creatinine increased – – – – 13 68
AE, adverse event; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; FD, flat dose; NCI-CTCAE, National Cancer
Institute Common Terminology Criteria for Adverse Events; RD, recommended dose.
Original article Annals of Oncology
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hypokalemia occurred. Severe hematological abnormalities com-
prised neutropenia (75% of patients), anemia (63%), leukopenia
and thrombocytopenia (50% each). All biochemical abnormal-
ities were grade 1/2.
Discussion
Remarkable antitumor activity was found for the doxorubicin/
PM01183 combination in relapsed SCLC. At the RD, ORR was
65% as second line (sensitive disease: 89%; resistant disease:
38%); and 50% as third line. Most responses occurred at the RD
and were durable. Median PFS was 5.8 months (sensitive disease)
and 3.5 months (resistant disease) as second line, and 1.2 months
as third line. Median duration of response was 4.5, 6.7 and
2.8 months, respectively. One CR lasted almost two years in a
patient with sensitive disease. Tumor shrinkage was maintained
in 88% of patients who switched to PM01183 alone.
Therapeutic options for SCLC relapsing after first-line therapy
are few. Currently approved second-line therapies resulted in
ORRs of 7%–44% (sensitive disease: 25%–53%; resistant disease:
10%–18%) and median PFS of 2.2–4.5 months in patients with
PFIs of 45–90 days or no brain metastases [10–12].
Immunotherapy drugs currently under evaluation for relapsed
SCLC have resulted in ORRs of 10%–33% for the monoclonal
antibody nivolumab alone or with ipilimumab [13] and 33%
for the monoclonal antibody pembrolizumab in selected patients
with PDL1-positive disease [14]. The antibody-drug conjugate
rovalpituzumab tesirine has been described to have an ORR of
18% in relapsed SCLC, with an ORR of 38% in highly selected pa-
tients with high DLL3 expression [15]. In contrast, in the present
study second-line doxorubicin/PM01183 combination resulted
in higher ORRs compared to currently approved therapies in un-
selected patients with sensitive (91.7%) and resistant (33.3%) dis-
ease. Median PFS was also longer. Of note, the 5.8 months
achieved with second-line doxorubicin/PM01183 in sensitive dis-
ease was similar to the median PFS of 5.5 months reported with
platinum/etoposide rechallenge in a retrospective analysis [16].
Remarkably, one-third of patients in this current study showed
longer PFS with second-line doxorubicin/PM01183 than with
first-line therapy.
Reversible myelosuppression was the most common toxicity
with the doxorubicin/PM01183 combination. Episodes of severe
neutropenia, thrombocytopenia and febrile neutropenia were
transient and successfully managed with cycle delays, dose reduc-
tions and colony-stimulating factors. Most other toxicities were
mild or moderate. Median dose intensities at the RD were 96%
for doxorubicin and 95% for PM01183. No toxic deaths
occurred.
Toxicities with doxorubicin/PM01183 were more frequent
than with single-agent PM01183 in a previous phase I study [5];
e.g. nausea/vomiting (58% versus 47%), mucositis (53% ver-
sus <10%) and alopecia (42% versus <10%). Severe hematolo-
gical toxicity was generally more frequent with doxorubicin/
PM01183 than with doxorubicin alone at 60 or 70 mg/m
2
q3wk
in other tumors [17,18] and similar than with approved second-
line therapies [19]. Some non-hematological toxicities were more
common with doxorubicin/PM01183 (anorexia, 53% versus
30%) than with doxorubicin alone; others occurred at similar
frequencies (nausea/vomiting, 58% versus 30%–75%; stomatitis/
mucositis, 53% versus 62%) or were less common (alopecia, 42%
versus 97%) [17,18]. The safety profile of single-agent PM01183
in this study generally agrees with that reported previously [5].
In summary, this doxorubicin/PM01183 q3wk regimen has re-
markable antitumor activity in relapsed SCLC that appears to be
meaningfully higher compared to standard second-line therapies,
particularly in sensitive disease. Tolerance suggested a positive
risk-benefit profile for doxorubicin/PM01183 in relapsed SCLC.
This trial is currently evaluating the combination in an expanded
cohort of SCLC patients at a reduced doxorubicin dose (40 mg/
m
2
) and with PM01183 transformed to a dose of 2.0 mg/m
2
to
improve safety over the profile described herein. An ongoing
randomized phase III trial is evaluating doxorubicin/PM01183
versus cyclophosphamide, doxorubicin and vincristine (CAV) or
topotecan, with primary colony-stimulating factor support as
second-line treatment of SCLC.
Funding
Pharma Mar S.A. (no grant numbers apply).
Disclosure
EC has been consultant for Novartis, Pierre Fabre, Boehringer
Ingelheim, EUSA and Seattle Genetics, and has participated in a
speaker’s bureau for Novartis. MPLC has been paid travel accom-
modation and expenses by Bristol. MF has been consultant for
Eli-Lilly, Pfizer, Clovis, Boehringer Ingelheim, Novartis, Merck,
AstraZeneca, BMS and MSD; has received research funding from
AstraZeneca and Boehringer Ingelheim; and has been paid travel
accommodation and expenses by Boehringer Ingelheim, BMS,
Celgene, Eli Lilly, Merck, MSD and Roche. In addition, MF is
supported by the UCL/UCLH NIHR Biomedical Research Centre
and runs early phase studies in the NIHR UCLH Clinical
Research Facility supported by the UCL ECMC. CK, MS, CFT,
MCY, and ASM-P are employees and stock owners of Pharma
Mar S.A. JAL-V is an employee of Pharma Mar S.A. All remaining
authors have declared no conflicts of interest.
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