Trial document




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  DRKS00011857

Trial Description

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Title

Phase III Randomized Clinical Trial of Lurbinectedin (PM01183) plus Doxorubicin (DOX) versus Topotecan as Treatment in Patients with Small-Cell Lung Cancer (SCLC) Who Failed One Prior Platinum-containing Line (ATLANTIS Trial)

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Trial Acronym

ATLANTIS

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URL of the Trial

[---]*

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Brief Summary in Lay Language

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. best Investigator’s choice between CAV or topotecan as a control arm, in SCLC patients who failed one prior platinumcontaining line but no more than one prior chemotherapy 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.

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Brief Summary in Scientific Language

Update due to protocol amendment, approved by RA on 02 Oct 2018, EC vote dated 18 Jul 2018.

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. best
Investigator’s choice between CAV or topotecan as a control arm, in SCLC patients who failed one prior platinumcontaining line but no more than one prior chemotherapycontaining 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.
An Independent Review Committee (IRC), blinded to the treatment assigned to the patients, 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.
The primary endpoint of the trial is the overall survival (OS).
Secondary endpoints comprise difference in OS between PM01183/DOX and CAV, in patients with CAV as best Investigator’s choice; OS/PFS per RECIST v.1.1 in patients with and without baseline central nervous system (CNS) involvement; PFS per RECIST v.1.1 by an IRC; best antitumor response as per RECIST v.1.1 and duration of response (DR) (both assessed by IRC); and safety profile. Tertiary endpoints comprise mid- and long-term survival assessed by measuring OS at 12/18/24 months, PFS per RECIST v.1.1 by IA, best antitumor response as per RECIST v.1.1 and DR (both assessed by IA), PRO, subgroup analyses, PK, PK/PDy correlations, and pharmacogenetics.

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Organizational Data

  •   DRKS00011857
  •   2017/03/14
  •   2015/09/24
  •   no
  •   Approved
  •   16/0299 - EK13, Ethik-Kommission des Landes Berlin
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Secondary IDs

  •   2015-001641-89 
  •   NCT02566993  (clinicaltrials.gov)
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Health Condition or Problem studied

  •   Small Cell Lung Cancer
  •   C34 -  Malignant neoplasm of bronchus and lung
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Interventions/Observational Groups

  •   Experimental: Test
    Lurbinectedin (PM01183) / Doxorubicin

    -DOX at 40.0 mg/m2 on Day 1, followed by,
    -PM01183 at 2.0 mg/m2 on Day 1 q3wk (three weeks ± 48 hours = one treatment cycle).
  •   Active Comparator: Topotecan or
    CAV (Cyclophosphamide (CTX), Doxorubicin (DOX) and Vincristine (VCR))
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Characteristics

  •   Interventional
  •   [---]*
  •   Randomized controlled trial
  •   Open (masking not used)
  •   [---]*
  •   Active control (effective treament of control group)
  •   Treatment
  •   Parallel
  •   III
  •   No
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Primary Outcome

Primary endpoint:
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 platinumcontaining line.

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Secondary Outcome

-Secondary endpoints:
To analyze:
o Difference in OS between PM01183/DOX and CAV, in patients with CAV as best Investigator’s choice.
o OS/PFS in patients with and without baseline central nervous system (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.
o Progression-free survival (PFS) by an Independent Review Committee (IRC).
o Antitumor activity by IRC according to the Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1.
o Safety profile.

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Countries of Recruitment

  •   Argentina
  •   Austria
  •   Belgium
  •   Bulgaria
  •   Brazil
  •   Canada
  •   Czech Republic
  •   Germany
  •   France
  •   Greece
  •   Hungary
  •   Italy
  •   Lebanon
  •   Netherlands
  •   Poland
  •   Portugal
  •   Spain
  •   United Kingdom
  •   United States
  •   Romania
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Locations of Recruitment

  • Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • Doctor's Practice 
  • University Medical Center 
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Recruitment

  •   Actual
  •   2016/08/30
  •   600
  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

1) Voluntary written informed consent of the patient obtained
before any study-specific procedure.
2) Adult patients aged ≥ 18 years.
3) Histologically or cytologically confirmed diagnosis of
limited or extensive stage SCLC which failed one prior
platinum-containing regimen and with a chemotherapy-free interval (CTFI, time from the last dose of first-line chemotherapy to the occurrence of progressive disease) ≥ 30 days.. Small-cell carcinoma of
unknown primary site with or without neuroendocrine
features confirmed in histology test(s) performed on
metastatic lesion(s) are eligible, if Ki-67/MIB-1 is
expressed in >50% of tumor cells.
4) ECOG PS ≤ 2.
5) Adequate hematological, renal, metabolic and hepatic
function in an assessment performed within 7 days (+ 3 day
window) of randomization:
a) Hemoglobin ≥ 9.0 g/dl [patients may have received prior
red blood cell (RBC) transfusion, if clinically indicated];
absolute neutrophil count (ANC) ≥ 2.0 x 109/l, and
platelet count ≥ 100 x 109/l.
b) Alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) ≤ 3.0 x upper limit of normal
(ULN).
c) Total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN.
d) Albumin ≥ 3.0 g/dl.
e) Calculated creatinine clearance (CrCL) ≥ 30 ml/minute
(using Cockcroft and Gault’s formula).
f) Left ventricular ejection fraction (LVEF) by
echocardiogram (ECHO) or multiple-gated acquisition
(MUGA) scan within normal range (according to
institutional standards).
g) Creatine phosphokinase (CPK) ≤ 2.5 x ULN (≤ 5.0 x
ULN is acceptable if elevation is disease-related).
6) At least three weeks since last prior anticancer treatment
and recovery to grade ≤ 1 from any adverse event (AE)
related to previous anticancer treatment (excluding sensory
neuropathy, anemia, asthenia and alopecia, all grade ≤ 2)
according to the National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI-CTCAE,
v.4).
7) Prior radiotherapy (RT): At least four weeks since
completion of whole-brain RT (WBRT), at least two weeks
since completion of prophylactic cranial irradiation (PCI),
and to any other site not previously specified.
8) Evidence of non-childbearing status for women of
childbearing potential (WOCBP). WOCBP must agree to
use a highly effective contraceptive measure up to six
weeks after treatment discontinuation. Fertile male patients with WOCBP partners should use condoms during treatment and for four months following the last investigational medicinal product (IMP) dose.

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Exclusion Criteria

1) More than one prior chemotherapy-containing regimen
(including patients re-challenged with same initial
regimen).
2) Patients who never received any platinum-containing
regimen for SCLC treatment.
3) Prior treatment with PM01183, topotecan or
anthracyclines.
4) Limited-stage patients who are candidates for local or
regional therapy, including PCI, thoracic RT or both, must
have been offered that option and completed treatment or
refused it prior to randomization.
5) Impending need for palliative RT or surgery for
pathological fractures and/or for medullary compression
within four weeks prior to randomization.
6) Symptomatic, or steroid-requiring, or progressing CNS
disease involvement during at least four weeks prior to
randomization (asymptomatic, non-progressing patients
taking steroids in the process of already being tapered
within two weeks prior to randomization are allowed).
7) Concomitant diseases/conditions:
a) History (within one year prior to randomization) or
presence of unstable angina, myocardial infarction,
congestive heart failure or clinically significant valvular
heart disease.
b) Symptomatic or uncontrolled arrhythmia despite
ongoing treatment.
c) Patients with any immunodeficiency, including those
known to be or have been infected by human
immunodeficiency virus (HIV).
d) Ongoing, treatment-requiring, non-neoplastic chronic
liver disease of any origin. For hepatitis B, this includes
positive tests for both Hepatitis B surface antigen
(HBsAg) and quantitative Hepatitis B polymerase chain
reaction (PCR). For hepatitis C, this includes positive
tests for both Hepatitis C antibody and quantitative
Hepatitis C PCR.
e) Active infection or increased risk due to external
drainages.
f) Intermittent or continuous oxygen requirement within
two weeks prior to randomization. Patients with
confirmed or suspected diagnosis of diffuse interstitial
lung disease (ILD) or pulmonary fibrosis.
g) Patients with a second invasive malignancy treated with
chemotherapy and/or RT. Patients with a previous
malignancy that was completely resected with curative
intention three or more years prior to randomization, and
who has been continuously in remission since then will
be permitted.
h) Limitation of the patient’s ability to comply with the treatment or to follow the protocol.
i) Documented or suspected invasive fungal infections
requiring systemic treatment within 12 weeks of
randomization.
8) Pregnant or breast feeding women.

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Addresses

  • start of 1:1-Block address primary-sponsor
    • Pharma Mar S.A.
    • Ms.  Ana Belén  Irigaray 
    • Avda de los Reyes, 1, Polígono Industrial "La Mina"
    • 28770  Colmenar Viejo (Madrid)
    • Spain
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    •   + 34 91 846 6000
    •   + 34 91 846 6003
    •   [---]*
    •   [---]*
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    • Pharma Mar S.A.
    • Ms.  Ana Belén  Irigaray 
    • Avda de los Reyes, 1, Polígono Industrial "La Mina"
    • 28770  Colmenar Viejo (Madrid)
    • Spain
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    • Pharma Mar S.A.
    • Ms.  Ana Belén  Irigaray 
    • Avda de los Reyes, 1, Polígono Industrial "La Mina"
    • 28770  Colmenar Viejo (Madrid)
    • Spain
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Sources of Monetary or Material Support

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    • Pharma Mar S.A.
    • Avda de los Reyes, 1, Polígono Industrial "La Mina"
    • 28770  Colmenar Viejo (Madrid)
    • Spain
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    •   + 34 91 846 6000
    •   + 34 91 846 6003
    •   [---]*
    •   [---]*
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Status

  •   Recruiting complete, follow-up continuing
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Trial Publications, Results and other Documents

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* This entry means the parameter is not applicable or has not been set.