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)

• Register: EUCTR
• Last refreshed on: 20 April 2020
• Main ID: EUCTR2015-001641-89-HU
• Date of registration: 10/05/2016
• Prospective Registration: Yes
• Primary sponsor: Pharma Mar S.A.
• Public title: 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)
• Scientific title: 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) - ATLANTIS trial
• Date of first enrolment: 28/06/2016
• Target sample size: 600
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-001641-89
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

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

Contacts

• Name: Clinical Trials
• Affiliation: Pharma Mar S.A.

• Name: Clinical Trials
• Affiliation: Pharma Mar S.A.

Key inclusion & exclusion criteria

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 priorred blood cell (RBC) transfusion, if clinically indicated]; absolute neutrophil count (ANC) = 2.0 x 10^9/l and platelet count = 100 x 10^9/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.
Valid methods to determine the childbearing potential, adequate contraception and requirements for WOCBP partners are described in the Appendix 2 of the protocol. Fertile male patients with WOCBP partners should use condoms during treatment and for four months following the last investigational medicinal product (IMP) dose.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 200
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 400

Exclusion criteria:
1) More than one prior CHT-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 CNSdisease 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 CHT 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.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Small-Cell Lung Cancer (SCLC)
MedDRA version: 20.0 Level: PT Classification code 10041067 Term: Small cell lung cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: lurbinectedin
Product Code: PM01183
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: lurbinectedin
CAS Number: 497871-47-3
Current Sponsor code: PM01183
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 4-

Trade Name: Doxorubicin-Aurobino 2 mg/ml Konzentrat zur Herstellung einer Infusionslösung
Product Name: doxorubicin
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: doxorubicin
CAS Number: 23214-92-8
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 2-

Trade Name: Topotecan Hospira 4 mg/4 ml concentrate for solution for infusion
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: topotecan
CAS Number: 123948-87-8
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1-

Trade Name: Cyclophosphamid Trockensubstanz 1 g Baxter Oncology
Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: CYCLOPHOSPHAMIDE
CAS Number: 50-18-0
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1000-

Trade Name: Vincristine Sulphate 1 mg/ml Injection
Pharmaceutical Form: Solution for injection
INN or Proposed INN: vincristine
CAS Number: 2068-78-2
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1-

Trade Name: DBL™ Vincristine Sulfate Injection
Pharmaceutical Form: Solution for injection
INN or Proposed INN: vincristine
CAS Number: 2068-78-2
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1-

Trade Name: ENDOXAN Lyophilisat 1 g Baxter Oncology
Pharmaceutical Form: Powder for solution for injectio

Primary Outcome(s)

Secondary Objective: Secondary
? 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
TERTIARY
? Mid- and long-term survival (OS at 12, 18 and 24 months)
? Efficacy and safety profiles in the subgroups of the PM01183/DOX arm vs. CAV or topotecan
? PFS by Investigator's Assessment (IA)
? Antitumor activity by IA according to the RECIST v.1.1
? Patient-reported outcomes
? PK of the combination in patients treated in the experimental arm
? PK/pharmacodynamic correlations in the experimental arm, if any
? Pharmacogenetics of known polymorphisms in patients treated in the experimental arm

Main 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.

Primary end point(s): Overall survival (OS) will be calculated from the date of randomization to the date of death (death event) or last contact (in this case, survival will be censored on that date).

Timepoint(s) of evaluation of this end point: Final OS analysis is planned 18 months after randomization of last patient (planned end of study date).

Secondary Outcome(s)

Secondary end point(s): SECONDARY ENDPOINTS
? Difference in OS between PM01183/DOX and CAV, in patients with CAV as best Investigator's choice.
? Overall survival (OS)/progression-free survival (PFS) per RECIST v.1.1 in patients with and without baseline CNS involvement. Subgroup analyses restricted to the sensitive and resistant populations will also be performed.
? Progression-free survival (PFS) by IRC
? Best antitumor response by IRC
? Duration of response (DR) by IRC
? Treatment safety profile
TERTIARY ENDPOINTS
? Mid- and long-term survival (OS at 12/18/24 months)
? Subgroup analyses
? Progression-free survival (PFS) per RECIST v.1.1 by IA.
? Best antitumor response by IA.
? Duration of response (DR) by IA.
? Patient-reported outcomes (PRO)
? Plasma pharmacokinetics (PK) of PM01183 and DOX.
? PK/pharmacodynamic (PDy) correlation.
? Pharmacogenetics.

Timepoint(s) of evaluation of this end point: Along the study

Secondary ID(s)

PM1183-C-003-14

Source(s) of Monetary Support

Pharma Mar S.A.

Ethics review

Status: Approved
Approval date: 17/06/2016
Contact: