Study Escalating Doses of PM01183 in Combination With Fixed Doxorubicin in Patients With Specific Advanced Unresectable Solid Tumors

• ClinicalTrials.gov Identifier: NCT01970540
• Recruitment Status: Completed
• First Posted: October 28, 2013
• Results First Posted: March 9, 2020
• Last Update Posted: March 9, 2020
• Sponsor: PharmaMar
• Information provided by (Responsible Party): PharmaMar

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.

Condition or disease	Intervention/treatment	Phase
Endometrial Adenocarcinomas; Neuroendocrine Tumors; Small-cell Lung Cancer With Less Than 2 Prior Cytotoxic-containing Lines of Therapy	Drug: lurbinectedin (PM01183); Drug: Doxorubicin	Phase 1

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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 122 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: May 25, 2011
• Actual Primary Completion Date: August 9, 2017
• Actual Study Completion Date: August 9, 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: lurbinectedin (PM01183) / doxorubicin	Drug: lurbinectedin (PM01183); lurbinectedin (PM01183) is presented as powder for concentrate for solution for infusion with two strengths, 1-mg and 4-mg vials.; Drug: Doxorubicin; Commercially available presentations of vials containing doxorubicin will be provided as appropriate.

Outcome Measures

Primary Outcome Measures :

1. Maximum Tolerated Dose (MTD) [ Time Frame: During the first cycle of treatment, up to 28 days ]
   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.
2. Recommended Dose (RD) [ Time Frame: During the first cycle of treatment, up to 28 days ]
   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.
3. Number of Participants With Dose-limiting Toxicities [ Time Frame: During the first cycle of treatment, up to 28 days ]
   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 :

1. Best Overall Tumor Response [ Time Frame: Tumor assessments were done every six weeks up to study completion ]
   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.
2. Duration of Response [ 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 ]
   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.
3. Progression-free Survival [ 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 ]
   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.
4. Overall Survival [ Time Frame: Time from the date of first administration to the date of death (of any cause), assessed up to 72 months ]
   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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

  1. Breast cancer
  2. Soft-tissue sarcoma
  3. Primary bone sarcomas.
  4. Gynecologic tumors (endometrial adenocarcinomas, epithelial ovarian cancer...)
  5. Hepatocellular carcinoma
  6. Gastroenteropancreatic neuroendocrine tumors
  7. Small cell lung cancer (SCLC)
  8. Gastric cancer
  9. Bladder cancer
  10. 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.

Contacts and Locations

Locations

Spain

Hospital Universitari Vall D'Hebron

Barcelona, Spain, 08035

Centro Oncológico Md Anderson International España

Madrid, Spain, 28033

Hospital Ramón Y Cajal

Madrid, Spain, 28034

Hospital Universitario Fundación Jiménez

Madrid, Spain, 28040

Hospital Universitario Madrid Sanchinarro

Madrid, Spain, 28050

Fundación Instituto Valenciano de Oncología

Valencia, Spain, 46009

United Kingdom

UCLH (University College London Hospitals)

London, United Kingdom, WC1E 6DB

Sponsors and Collaborators

PharmaMar

  Study Documents (Full-Text)

Documents provided by PharmaMar:

Study Protocol  [PDF] October 17, 2014

Statistical Analysis Plan  [PDF] February 12, 2018

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Olmedo ME, Forster M, Moreno V, López-Criado MP, Braña I, Flynn M, Doger B, de Miguel M, López-Vilariño JA, Núñez 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.

• Responsible Party: PharmaMar
• ClinicalTrials.gov Identifier: NCT01970540
• Other Study ID Numbers: PM1183-A-003-10
• First Posted: October 28, 2013
• Results First Posted: March 9, 2020
• Last Update Posted: March 9, 2020
• Last Verified: January 2020

Keywords provided by PharmaMar:

lurbinectedin; PM01183; tumors; cancer; Pharma Mar

Additional relevant MeSH terms:

Small Cell Lung Carcinoma; Neuroendocrine Tumors; Neoplasms; Neoplasms by Histologic Type; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Doxorubicin; Antibiotics, Antineoplastic; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action