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Trial record 1 of 1 for:    LUPER_MedOPP300
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Lurbinectedin (PM01183) Combined With Pembrolizumab in Small Cell Lung Cancer. (LUPER)

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ClinicalTrials.gov Identifier: NCT04358237
Recruitment Status : Recruiting
First Posted : April 24, 2020
Last Update Posted : October 19, 2020
Sponsor:
Collaborators:
MedSIR
PharmaMar
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Antonio Calles Blanco, Blanco, Dr Antonio Calles MD

Brief Summary:

This is a prospective, open-label, uncontrolled and multicenter phase I/II study of PM01183 in combination with pembrolizumab in patients with relapsed small cell lung cancer (SCLC).

The study will be divided into two stages:

  • A dose-ranging phase I stage with escalating doses of PM01183 in combination with a fixed dose of pembrolizumab, followed by:
  • A non-randomized phase II stage as an expansion study at the recommended dose (RD) determined during the phase I stage.

The phase I stage will focus on the selection of the RD based on safety/tolerability, while the phase II stage will assess the overall response rate (ORR) and clinical response.


Condition or disease Intervention/treatment Phase
Small Cell Lung Carcinoma Drug: Lurbinectedin Drug: Pembrolizumab Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Phase I/II, Multicenter, Open-label, Clinical and Pharmacokinetic Study of Lurbinectedin (PM01183) in Combination with Pembrolizumab in Patients with Relapsed Small Cell Lung Cancer
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II, Multicenter, Open-label, Clinical and Pharmacokinetic Study of Lurbinectedin (PM01183) in Combination With Pembrolizumab in Patients With Relapsed Small Cell Lung Cancer
Actual Study Start Date : September 21, 2020
Estimated Primary Completion Date : March 31, 2023
Estimated Study Completion Date : August 31, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Experimental: lurbinectedin (PM01183) + pembrolizumab

During the phase I stage, patients will start receiving pembrolizumab at a fixed dose of 200 mg as a 30-min intravenous (IV) infusion followed by lurbinectedin at a starting dose of 2.4 mg/m2 as a 1-h IV infusion on Day 1, both every 3 weeks (Q3W). Lurbinectedin dose will be escalated from the starting dose in successive cohorts of patients, with a pre-established fixed dose increase (in mg/m2) of approximately 30%.

During the phase II stage, patients will receive pembrolizumab at a fixed dose of 200 mg as a 30-min IV infusion followed by lurbinectedin as a 1-h IV infusion on Day 1 Q3W at the redommended dose (RD) determined during the phase I stage. A cycle is defined as an interval of 3 weeks. No dose escalation will be allowed during the phase II stage.

Drug: Lurbinectedin

Lurbinectedin will be presented as a lyophilized powder for concentrate for solution for infusion in 4-mg vials. Before use, the 4-mg vial will be reconstituted with 8 mL of sterile water for injection, to give a solution containing 0.5 mg/mL of PM01183. For administration to patients as IV infusion, reconstituted vials will be diluted with glucose 50 mg/mL (5%) or sodium chloride 9 mg/mL (0.9%) solution for infusion.

PM01183 will be administered as a 1 hour IV infusion Q3W, in a minimum volume of 100 mL of solution for infusion (either 5% glucose or 0.9% sodium chloride), or a minimum volume of 250 mL if through a peripheral line, always at a fixed rate and through a pump device.

Other Names:
  • PM01183
  • Zepsyre

Drug: Pembrolizumab
Pembrolizumab will be supplied as a solution for infusion in a single-use vial. Each vial contains 100 mg of MK3475 (pembrolizumab) in 4 ml of solution. Pembrolizumab 200 mg will be administered as a 30 minute IV infusion Q3W.
Other Name: Keytruda




Primary Outcome Measures :
  1. Phase I: Maximum tolerated dose (MTD) and recommended phase II dose (RD) of lurbinectedin in combination with pembrolizumab in patients with relapsed SCLC. [ Time Frame: 12 months ]
    The MTD will be the lowest dose level explored during dose escalation at which more than one third of evaluable patients develop a DLT in Cycle 1. The RD will be the highest dose level explored at which less than one third of evaluable patients develop a DLT during Cycle 1.

  2. Phase II: Efficacy of lurbinectedin in combination with pembrolizumab in terms of overall response rate (ORR), according to RECIST 1.1, in patients with relapsed SCLC. [ Time Frame: 38 months ]

    ORR is defined as the percentage of evaluable patients with a confirmed response, either complete (CR) or partial (PR).

    The ORR will be assessed using the RECIST 1.1 on a set of measurable lesions identified at baseline as target lesions or as non-target lesions (if any), and followed until PD by an appropriate method.



Secondary Outcome Measures :
  1. Phase I: Preliminary information on the clinical antitumor activity of the combination. [ Time Frame: 28 months ]
    Preliminary antitumor activity in the phase I stage will be evaluated according to the RECIST 1.1 (and the iRECIST 1.1, whenever applicable) at least 6 weeks after treatment initiation in all patients with measurable disease.

  2. Phase I: MTD and RD of lurbinectedin in combination with pembrolizumab with mandatory primary prophylaxis with G-CSF in patients with relapsed SCLC (if DLTs of this combination are exclusively related to neutropenia). [ Time Frame: 12 months ]
    The MTD will be the lowest dose level explored during dose escalation at which more than one third of evaluable patients develop a DLT in Cycle 1. The RD will be the highest dose level explored at which less than one third of evaluable patients develop a DLT during Cycle 1.

  3. Phase II: Antitumor activity of this combination as per RECIST 1.1 (and iRECIST 1.1, whenever applicable) in terms of Clinical benefit ≥3 months. [ Time Frame: 38 months ]
    During expansion at the RD in the phase II stage, antitumor activity will also be evaluated according to the RECIST 1.1 (and the iRECIST 1.1, whenever applicable).

  4. Phase II: Antitumor activity of this combination as per RECIST 1.1 (and iRECIST 1.1, whenever applicable) in terms of Duration of response (DOR). [ Time Frame: 38 months ]
    During expansion at the RD in the phase II stage, antitumor activity will also be evaluated according to the RECIST 1.1 (and the iRECIST 1.1, whenever applicable).

  5. Phase II: Antitumor activity of this combination as per RECIST 1.1 (and iRECIST 1.1, whenever applicable) in terms of Progression-free survival (PFS). [ Time Frame: 38 months ]
    During expansion at the RD in the phase II stage, antitumor activity will also be evaluated according to the RECIST 1.1 (and the iRECIST 1.1, whenever applicable).

  6. Phase II: Antitumor activity of this combination as per RECIST 1.1 (and iRECIST 1.1, whenever applicable) in terms of Overall survival (OS). [ Time Frame: 38 months ]
    During expansion at the RD in the phase II stage, antitumor activity will also be evaluated according to the RECIST 1.1 (and the iRECIST 1.1, whenever applicable).

  7. Both Stages: Safety profile and feasibility of lurbinectedin in combination with pembrolizumab in patients with relapsed SCLC. [ Time Frame: 38 months ]
    Patients will be evaluable for safety if they have received at least one partial infusion of lurbinectedin. AEs will be graded according to the NCI-CTCAE v.5. Additionally, treatment compliance, in particular dose reduction requirements, skipped doses and/or cycle delays due to AEs, will be described.

  8. Both stages: Characterize the plasma pharmacokinetics (PK) of lurbinectedin in this combination and to detect major drug-drug PK interactions. [ Time Frame: 38 months ]
    PK parameters (CMax) will be evaluated in plasma by standard non-compartmental methods (compartmental modeling may be performed if appropriate).

  9. Both stages: Pharmacogenetic (PGt) analysis. [ Time Frame: 38 months ]
    A blood sample will be collected at any time during the trial (but preferably just before treatment start in Cycle 1 along with the first PK sample) to analyze germline DNA for the presence or absence of mutations or polymorphisms in genes relevant for the metabolism and/or transport of lurbinectedin that may help explain individual variability in main PK parameters.

  10. Both stages: Pharmacogenomic (PGx) analysis in tumor samples of patients exposed to lurbinectedin and pembrolizumab in order to assess potential markers of response and/or resistance. [ Time Frame: 38 months ]
    The mutational status of factors involved in DNA repair mechanisms, or related to the mechanism of action of PM01183 or pembrolizumab, will be evaluated from available prior paraffin-embedded tumor tissue samples obtained at diagnosis or relapse. mRNA and/or protein expression levels of these factors might be also analyzed, if relevant. Potentially whole exome sequencing will also be analyzed. Their correlation with the clinical response and outcome after treatment will be assessed.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of SCLC whose disease has progressed after first-line chemotherapy-based regimen will be enrolled in this study.
  • At least 4 weeks since the last anticancer therapy.
  • Male participants: a male participant must agree to use a contraception as detailed in the study protocol during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period.
  • Female participants: a female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies:

    1. Not a woman of childbearing potential (WOCBP) OR
    2. A WOCBP who agrees to follow the contraceptive guidance as detailed in the study protocol during the treatment period and for at least 90 days after the last dose of study treatment.
  • The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
  • Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
  • Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1. Evaluation of ECOG PS is to be performed within 7 days prior to the date of allocation/randomization.
  • Have adequate organ function.
  • Recovery to NCI-CTCAE grade ≤1 or to baseline from any AE derived from previous treatment (excluding alopecia and/or cutaneous toxicity and/or peripheral sensory neuropathy and/or asthenia, all grade ≤2 and/or correctable electrolyte abnormality with supplementation).
  • Patients included in the expansion cohort at the RD (phase I stage) and all patients included in the phase II stage must have:

    1. Measurable disease according to RECIST 1.1; and
    2. Documented disease progression during or immediately after last therapy according to any of the aforementioned criteria.

Exclusion Criteria:

  • A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  • Has had prior treatment with or exposure to:

    1. Lurbinectedin.
    2. Radioimmunoconjugates.
    3. T-cell or other cell-based or biologic therapies.
    4. Experimental anti-tumor vaccines; therapies that target any T-cell co-stimulation or checkpoint pathways, such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti CTLA-4 antibody, including ipilimumab; or other medicines specifically targeting T-cells.
  • Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to allocation.

Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.

Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.

  • Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
  • Has had radiotherapy (RT) in more than 35% of the bone marrow.
  • Has a history of previous bone marrow and/or stem cell transplantation and allogenic transplant.
  • Has an impending need for RT (e.g., painful bone metastasis and/or risk of spinal cord compression).
  • Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
  • Has any of the following concomitant diseases/conditions:

    1. History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular heart disease within last year.
    2. Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment.
    3. History of idiopathic, pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis or evidence of active pneumonitis on screening chest CT-scan. History of radiation pneumonitis in radiation field (fibrosis) is permitted, as long as it is asymptomatic and no steroids are needed.
    4. Known history of active neurologic paraneoplastic syndrome.
    5. Myopathy or any clinical situation that causes significant and persistent elevation of CPK (>2.5 x ULN in two different determinations performed one week apart).
    6. Limitation of the patient's ability to comply with the treatment or follow-up protocol.
    7. Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in this study.
  • Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.

Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.

  • Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
  • Has a known additional malignancy that is progressing or has required active treatment within the past 5 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
  • Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment. Brain CT-scan or MRI results must be provided at baseline.
  • Has severe hypersensitivity (≥Grade 3) to pembrolizumab, lubinectedin and/or any of their excipients.
  • Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Exception: patients with vitiligo or resolved childhood asthma/atopy; patients who require intermittent use of bronchodilators or local steroid injections; and patients with hypothyroidism stable on hormone replacement or Sjögren's syndrome will not be excluded from the study.
  • Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
  • Has an active infection requiring systemic therapy.
  • Has a known history of Human Immunodeficiency Virus (HIV).
  • Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
  • Has a known history of active tuberculosis (Mycobacterium tuberculosis).
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04358237


Contacts
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Contact: Gemma Martinez Masana 932214135 gemma.martinez@medsir.org
Contact: Carolina Herrero 932214135 regulatory@medsir.org

Locations
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Spain
Hospital Gregorio Marañon Recruiting
Madrid, Spain
Contact    914269394      
START - Phase I Unit - HN San Chinarro Recruiting
Madrid, Spain
Contact    917567828      
Start - Unidad Fase I - Fundacion Jimenez Diaz Recruiting
Madrid, Spain
Contact    91 550 48 00      
Sponsors and Collaborators
Antonio Calles Blanco
MedSIR
PharmaMar
Merck Sharp & Dohme Corp.
Investigators
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Principal Investigator: Antonio Calles Hospital Gregorio Marañon
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Responsible Party: Antonio Calles Blanco, Physician Thoracic Oncology, Head & Neck and Sarcoma Unit Early Drug Development and Phase I Unit, Blanco, Dr Antonio Calles MD
ClinicalTrials.gov Identifier: NCT04358237    
Other Study ID Numbers: MedOPP300
First Posted: April 24, 2020    Key Record Dates
Last Update Posted: October 19, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Antonio Calles Blanco, Blanco, Dr Antonio Calles MD:
Relapsed
Additional relevant MeSH terms:
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Small Cell Lung Carcinoma
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents