Back to resultsStudy Escalating Doses of PM01183 in Combination With Fixed Doxorubicin in Patients With Specific Advanced Unresectable Solid Tumors
Primary Purpose
Endometrial Adenocarcinomas, Neuroendocrine Tumors, Small-cell Lung Cancer With Less Than 2 Prior Cytotoxic-containing Lines of Therapy
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
lurbinectedin (PM01183)
Doxorubicin
Sponsored by
About this trial
This is an interventional treatment trial for Endometrial Adenocarcinomas focused on measuring lurbinectedin, PM01183, tumors, cancer, Pharma Mar
Eligibility Criteria
Inclusion Criteria:
- Voluntarily written informed consent
- Age: between 18 and 75 years (both inclusive).
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1. Cohort of patients with SCLC and endometrial cáncer ECOG PS ≤ 2.
- Life expectancy ≥ 3 months.
Patients with a histologically/cytologically confirmed diagnosis of advanced disease of any of the following tumors:
- Breast cancer
- Soft-tissue sarcoma
- Primary bone sarcomas.
- Gynecologic tumors (endometrial adenocarcinomas, epithelial ovarian cancer...)
- Hepatocellular carcinoma
- Gastroenteropancreatic neuroendocrine tumors
- Small cell lung cancer (SCLC)
- Gastric cancer
- Bladder cancer
- Adenocarcinoma of unknown primary site
- At least three weeks since the last anticancer therapy, including radiotherapy
- Adequate bone marrow, renal, hepatic, and metabolic function
- Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan within normal range (according to institutional standards).
- Women of childbearing potential must have a negative serum pregnancy test before study entry. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for six weeks after discontinuation of treatment
Exclusion Criteria:
Concomitant diseases/conditions:
- History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular heart disease within last year.
- Symptomatic or any uncontrolled arrhythmia
- Ongoing chronic alcohol consumption, or cirrhosis
- Active uncontrolled infection.
- Known human immunodeficiency virus (HIV) infection.
- Any other major illness that, in the Investigator's judgment
- Brain metastases or leptomeningeal disease involvement.
- Men or women of childbearing potential who are not using an effective method of contraception
- Patients who have had radiation therapy in more than 35% of the bone marrow. This criterion will not apply to cohort of patients with SCLC and endometrial cáncer.
- History of previous bone marrow and/or stem cell transplantation.
Sites / Locations
- Hospital Universitari Vall D'Hebron
- Centro Oncológico Md Anderson International España
- Hospital Ramón Y Cajal
- Hospital Universitario Fundación Jiménez
- Hospital Universitario Madrid Sanchinarro
- Fundación Instituto Valenciano de Oncología
- UCLH (University College London Hospitals)
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
lurbinectedin (PM01183) / doxorubicin
Arm Description
Outcomes
Primary Outcome Measures
Maximum Tolerated Dose (MTD)
A minimum of three patients will be included at each DL. If no patients experience a DLT during Cycle 1, the dose will be escalated. If one of three patients experiences a DLT, three additional patients will be included at that level. If >1 evaluable patient during dose escalation at a given DL experience a DLT during Cycle 1, that DL will be considered the MTD and dose escalation will be terminated, except if all DLTs are related to neutropenia exclusively, in which case dose escalation may be resumed as originally planned in a new cohort of patients but with compulsory primary G-CSF prophylaxis.
Recommended Dose (RD)
The DL immediately below the MTD, or DL4 if the MTD is not yet defined during dose escalation before the last DL (i.e., DL4) is reached, was to be initially expanded up to a minimum of nine evaluable patients. If less than three among the first nine evaluable patients treated within the expansion cohort experience a DLT during Cycle 1, this DL will be the RD.
Number of Participants With Dose-limiting Toxicities
DLT,dose-limiting toxicity Patients enrolled into this study were originally not allowed to receive primary G-CSF prophylaxis. However, the finding of dose-limiting febrile neutropenia in two patients treated at dose level I in the present study (see below) suggested that increasing doses of the DOX/PM01183 combination might require primary G-CSF prophylaxis to decrease the risk of febrile neutropenia. Therefore, a separate dose escalation was established to define the MTD and the RD of the DOX/PM01183 combination with compulsory primary G-CSF prophylaxis.
Secondary Outcome Measures
Best Overall Tumor Response
Tumor response was evaluated according to the RECIST v.1.1 for target lesions and assessed by computed tomography (CT) scans or magnetic resonance imagings (MRIs): Progressive disease (PD) is declared when there is an increase in sum of target disease ≥ 20%, stable diease (SD) when the change is > -30% and ≤ 20%, partial response (PR) when there is a decrease in sum of target disease ≥ 30%, and complete response (CR) when all lesions have disappeared or all lesions have disapeared and all nodal disease is < 10 mm each.
Duration of Response
The duration of overall response was measured from the time measurement criteria are met for complete response (CR)/ PR, whichever is first recorded, until the first date in which progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started) or the date of death. In absence of disease progression or death, the duration of response was censored on the date of last tumor evaluation.
Progression-free Survival
Progression-free survival (PFS) is defined as the time from the date of first infusion of study treatment to the date of progression or death (due to any cause). If progression or death has not occurred at the time of the analysis, the PFS was censored on the date of last tumor evaluation.
Overall Survival
Overall survival (OS) is defined as the time from the date of first infusion of study treatment to the date of death (due to any cause). Patients with no documented death were censored at the last date they are known to be alive
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01970540
Brief Title
Study Escalating Doses of PM01183 in Combination With Fixed Doxorubicin in Patients With Specific Advanced Unresectable Solid Tumors
Official Title
Phase I Multicenter, Open-label, Clinical and Pharmacokinetic Study of PM01183 in Combination With Doxorubicin in Non-heavily Pretreated Patients With Selected Advanced Solid Tumors
Study Type
Interventional
2. Study Status
Record Verification Date
January 2020
Overall Recruitment Status
Completed
Study Start Date
May 25, 2011 (Actual)
Primary Completion Date
August 9, 2017 (Actual)
Study Completion Date
August 9, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
PharmaMar
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
Phase I Multicenter, Open-label, Clinical and Pharmacokinetic Study of PM01183 in Combination with Fixed Doxorubicin in Non- Heavily Pretreated Patients with Selected Advanced Solid Tumors to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of PM01183 in combination with doxorubicin, to characterize the safety profile and feasibility of this combination, to characterize the pharmacokinetics (PK) of this combination, to obtain preliminary information on the clinical antitumor activity,to explore the feasibility, safety and efficacy of a potential improvable dose of this combination in selected tumor types [i.e. small cell lung cancer (SCLC) and endometrial cáncer] and to evaluate the pharmacogenomics (PGx) in tumor samples of patients exposed to PM01183 and doxorubicin at the RD in order to assess potential markers of response and/or resistance.
Detailed Description
The study has currently met its primary end point and is now recruiting patients to be treated at the RD expansion cohort of selected tumor types, specifically: endometrial adenocarcinomas, neuroendocrine tumors, and small-cell lung cancer (SCLC).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Endometrial Adenocarcinomas, Neuroendocrine Tumors, Small-cell Lung Cancer With Less Than 2 Prior Cytotoxic-containing Lines of Therapy
Keywords
lurbinectedin, PM01183, tumors, cancer, Pharma Mar
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
122 (Actual)
8. Arms, Groups, and Interventions
Arm Title
lurbinectedin (PM01183) / doxorubicin
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
lurbinectedin (PM01183)
Intervention Description
lurbinectedin (PM01183) is presented as powder for concentrate for solution for infusion with two strengths, 1-mg and 4-mg vials.
Intervention Type
Drug
Intervention Name(s)
Doxorubicin
Intervention Description
Commercially available presentations of vials containing doxorubicin will be provided as appropriate.
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose (MTD)
Description
A minimum of three patients will be included at each DL. If no patients experience a DLT during Cycle 1, the dose will be escalated. If one of three patients experiences a DLT, three additional patients will be included at that level. If >1 evaluable patient during dose escalation at a given DL experience a DLT during Cycle 1, that DL will be considered the MTD and dose escalation will be terminated, except if all DLTs are related to neutropenia exclusively, in which case dose escalation may be resumed as originally planned in a new cohort of patients but with compulsory primary G-CSF prophylaxis.
Time Frame
During the first cycle of treatment, up to 28 days
Title
Recommended Dose (RD)
Description
The DL immediately below the MTD, or DL4 if the MTD is not yet defined during dose escalation before the last DL (i.e., DL4) is reached, was to be initially expanded up to a minimum of nine evaluable patients. If less than three among the first nine evaluable patients treated within the expansion cohort experience a DLT during Cycle 1, this DL will be the RD.
Time Frame
During the first cycle of treatment, up to 28 days
Title
Number of Participants With Dose-limiting Toxicities
Description
DLT,dose-limiting toxicity Patients enrolled into this study were originally not allowed to receive primary G-CSF prophylaxis. However, the finding of dose-limiting febrile neutropenia in two patients treated at dose level I in the present study (see below) suggested that increasing doses of the DOX/PM01183 combination might require primary G-CSF prophylaxis to decrease the risk of febrile neutropenia. Therefore, a separate dose escalation was established to define the MTD and the RD of the DOX/PM01183 combination with compulsory primary G-CSF prophylaxis.
Time Frame
During the first cycle of treatment, up to 28 days
Secondary Outcome Measure Information:
Title
Best Overall Tumor Response
Description
Tumor response was evaluated according to the RECIST v.1.1 for target lesions and assessed by computed tomography (CT) scans or magnetic resonance imagings (MRIs): Progressive disease (PD) is declared when there is an increase in sum of target disease ≥ 20%, stable diease (SD) when the change is > -30% and ≤ 20%, partial response (PR) when there is a decrease in sum of target disease ≥ 30%, and complete response (CR) when all lesions have disappeared or all lesions have disapeared and all nodal disease is < 10 mm each.
Time Frame
Tumor assessments were done every six weeks up to study completion
Title
Duration of Response
Description
The duration of overall response was measured from the time measurement criteria are met for complete response (CR)/ PR, whichever is first recorded, until the first date in which progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started) or the date of death. In absence of disease progression or death, the duration of response was censored on the date of last tumor evaluation.
Time Frame
Time from the time measurement criteria are met for complete response, whichever is first recorded, until the first date in which progressive disease is objectively documented or the date of death, assessed up to 72 months
Title
Progression-free Survival
Description
Progression-free survival (PFS) is defined as the time from the date of first infusion of study treatment to the date of progression or death (due to any cause). If progression or death has not occurred at the time of the analysis, the PFS was censored on the date of last tumor evaluation.
Time Frame
Time from the date of first administration to the date of PD or death (of any cause), whichever came first, assessed up to 72 months
Title
Overall Survival
Description
Overall survival (OS) is defined as the time from the date of first infusion of study treatment to the date of death (due to any cause). Patients with no documented death were censored at the last date they are known to be alive
Time Frame
Time from the date of first administration to the date of death (of any cause), assessed up to 72 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Voluntarily written informed consent
Age: between 18 and 75 years (both inclusive).
Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1. Cohort of patients with SCLC and endometrial cáncer ECOG PS ≤ 2.
Life expectancy ≥ 3 months.
Patients with a histologically/cytologically confirmed diagnosis of advanced disease of any of the following tumors:
Breast cancer
Soft-tissue sarcoma
Primary bone sarcomas.
Gynecologic tumors (endometrial adenocarcinomas, epithelial ovarian cancer...)
Hepatocellular carcinoma
Gastroenteropancreatic neuroendocrine tumors
Small cell lung cancer (SCLC)
Gastric cancer
Bladder cancer
Adenocarcinoma of unknown primary site
At least three weeks since the last anticancer therapy, including radiotherapy
Adequate bone marrow, renal, hepatic, and metabolic function
Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan within normal range (according to institutional standards).
Women of childbearing potential must have a negative serum pregnancy test before study entry. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for six weeks after discontinuation of treatment
Exclusion Criteria:
Concomitant diseases/conditions:
History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular heart disease within last year.
Symptomatic or any uncontrolled arrhythmia
Ongoing chronic alcohol consumption, or cirrhosis
Active uncontrolled infection.
Known human immunodeficiency virus (HIV) infection.
Any other major illness that, in the Investigator's judgment
Brain metastases or leptomeningeal disease involvement.
Men or women of childbearing potential who are not using an effective method of contraception
Patients who have had radiation therapy in more than 35% of the bone marrow. This criterion will not apply to cohort of patients with SCLC and endometrial cáncer.
History of previous bone marrow and/or stem cell transplantation.
Facility Information:
Facility Name
Hospital Universitari Vall D'Hebron
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Facility Name
Centro Oncológico Md Anderson International España
City
Madrid
ZIP/Postal Code
28033
Country
Spain
Facility Name
Hospital Ramón Y Cajal
City
Madrid
ZIP/Postal Code
28034
Country
Spain
Facility Name
Hospital Universitario Fundación Jiménez
City
Madrid
ZIP/Postal Code
28040
Country
Spain
Facility Name
Hospital Universitario Madrid Sanchinarro
City
Madrid
ZIP/Postal Code
28050
Country
Spain
Facility Name
Fundación Instituto Valenciano de Oncología
City
Valencia
ZIP/Postal Code
46009
Country
Spain
Facility Name
UCLH (University College London Hospitals)
City
London
ZIP/Postal Code
WC1E 6DB
Country
United Kingdom
12. IPD Sharing Statement
Citations:
PubMed Identifier
33704620
Citation
Olmedo ME, Forster M, Moreno V, Lopez-Criado MP, Brana I, Flynn M, Doger B, de Miguel M, Lopez-Vilarino JA, Nunez R, Kahatt C, Cullell-Young M, Zeaiter A, Calvo E. Efficacy and safety of lurbinectedin and doxorubicin in relapsed small cell lung cancer. Results from an expansion cohort of a phase I study. Invest New Drugs. 2021 Oct;39(5):1275-1283. doi: 10.1007/s10637-020-01025-x. Epub 2021 Mar 11.
Results Reference
derived
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Study Escalating Doses of PM01183 in Combination With Fixed Doxorubicin in Patients With Specific Advanced Unresectable Solid Tumors
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