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Lurbinectedin With Berzosertib, an ATR Kinase Inhibitor in Small Cell Cancers and High-Grade Neuroendocrine Cancers

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ClinicalTrials.gov Identifier: NCT04802174
Recruitment Status : Recruiting
First Posted : March 17, 2021
Last Update Posted : December 7, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

Small cell lung cancer (SCLC) and high-grade neuroendocrine cancers (HGNEC) are aggressive neuroendocrine cancers. At first, SCLC and HGNEC respond to chemotherapy. But then they relapse quickly and become resistant to treatment. Researchers want to see if a combination of drugs can help.

Objective:

To see if the combination of lurbinectedin and berzosertib may be effective to shrink SCLC and HGNEC tumors, and to find the best dose of the combination.

Eligibility:

Adults ages 18 and older with a solid tumor, SCLC, or HGNEC.

Design:

Participants will get lurbinectedin by intravenous (IV) catheter on Day 1 of each cycle (1 cycle = 21 days). They will get berzosertib by IV on Days 1 and 2 of each cycle.

Participants will continue to receive treatment as long as they are benefiting from treatment.

Participants will have physical exams and blood tests. Their symptoms, medicines, and ability to perform their normal activities will be reviewed.

Participants will have electrocardiograms to test heart function. Sticky pads will be placed on their chest, arms, and legs.

Participants will give blood and hair samples for research. They may have optional tumor biopsies.

Participants will have computed tomography (CT) scans to see if the treatment is effective.

Participants will have a follow-up visit 1 month after treatment ends. Then they will be followed by email or phone for the rest of their life.


Condition or disease Intervention/treatment Phase
SCLC Small Cell Cancer Advanced Solid Tumor High Grade Neuroendocrine Cancers Drug: Lurbinectedin Drug: Berzosertib Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 75 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Trial of Lurbinectedin With Berzosertib, an ATR Kinase Inhibitor in Small Cell Cancers and High Grade Neuroendocrine Cancers
Actual Study Start Date : June 1, 2021
Estimated Primary Completion Date : August 1, 2025
Estimated Study Completion Date : December 1, 2026

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 1/ Phase I
Dose escalation of Berzosertib + lurbinectedin
Drug: Lurbinectedin
Participants meeting inclusion and exclusion criteria will receive lurbinectedin (on day 1) and berzosertib (on day 1 and 2) administered every 21 days (1 cycle), either in the in-patient or out-patient setting, until disease progression or development of intolerable side effects.

Drug: Berzosertib
Participants meeting inclusion and exclusion criteria will receive lurbinectedin (on day 1) and berzosertib (on day 1 and 2) administered every 21 days (1 cycle), either in the in-patient or out-patient setting, until disease progression or development of intolerable side effects.

Experimental: 2/ Phase II
Berzosertib + lurbinectedin at MTD
Drug: Lurbinectedin
Participants meeting inclusion and exclusion criteria will receive lurbinectedin (on day 1) and berzosertib (on day 1 and 2) administered every 21 days (1 cycle), either in the in-patient or out-patient setting, until disease progression or development of intolerable side effects.

Drug: Berzosertib
Participants meeting inclusion and exclusion criteria will receive lurbinectedin (on day 1) and berzosertib (on day 1 and 2) administered every 21 days (1 cycle), either in the in-patient or out-patient setting, until disease progression or development of intolerable side effects.




Primary Outcome Measures :
  1. MTD [ Time Frame: Phase I ]
    Maximum tolerated dose (MTD) of lurbinectedin in combination with berzosertib.

  2. Clinical response rate [ Time Frame: Phase II ]
    - Fraction of participants who experience a PR or CR in each cohort reported along with a 95% confidence interval. - Overall response rate for both cohorts combined, along with a 95% confidence interval.


Secondary Outcome Measures :
  1. Safety and tolerability [ Time Frame: Phase I ]
    Dose level Adverse Events (AE) per CTCAE v5.0, by type and grade of toxicity.

  2. Pharmacodynamic markers of response [ Time Frame: Phase I ]
    GammaH2ax and POLII as possible markers for pharmacodynamic activity and evaluation of changes in the markers between baseline and end of treatment vs. response

  3. Pharmacokinetic profile of Berzosertib and Lurbinectedin [ Time Frame: Phase I ]
    This will be evaluated using descriptive methods and reported as exploratory results. If any statistical tests are performed in these analyses, the results will be presented without adjustment for multiple comparisons but reported in the context of the number of tests performed.

  4. Progression-free survival (PFS) [ Time Frame: Phase II ]
    - Progression free survival will be determined from the on-study date until date of progression or death without progression, separately by cohort.

  5. Overall survival (OS) [ Time Frame: Phase II ]
    - Overall survival determined from the on-study date until date of death or last follow-up, separately by phase II cohort.

  6. Duration of response [ Time Frame: Phase II ]
    Duration of response to the combination in both platinum sensitive and refractory participants

  7. Safety and tolerability of the MTD [ Time Frame: Phase II ]
    Grades and types of toxicity will be reported for all patients treated at the DLT.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:
  • Both Phase I and Phase II:
  • Male and female, greater than or equal to 18 years of age.
  • ECOG performance status less than or equal to 2
  • Measurable disease, per RECIST 1.1. Individuals with evaluable, but not measurable disease will be eligible for Phase I.
  • Adequate organ functions

    • Hemoglobin greater than or equal to 9.0 g/dL
    • Absolute neutrophil count greater than or equal to 1.5x10(9)/L
    • Platelets greater than or equal to 100x10(9)/L
    • Total Bilirubin less than or equal to 2.0 mg/dL
    • Transaminases less than or equal to 2 x ULN or if liver metastases were present, less than or equal to 3 x ULN
    • Creatinine less than or equal to 1.5 mg/dL or creatinine clearance by Cockcroft-Gault formula greater than or equal to 60 mL/min
  • Ability to understand and the willingness to sign a written informed consent document.
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during study participation and for 6 months after the last dose study therapy. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

Phase I:

  • Histologically confirmed advanced solid cancers will be eligible.
  • At least one prior chemotherapy

Phase II:

- Histological confirmation of SCLC or HGNEC. Although NCI confirmation of pathology is not required prior to starting treatment, every effort will be made to obtain outside pathology to be reviewed by an NCI pathologist.

EXCLUSION CRITERIA:

  • Individuals with tumor amenable to potentially curative therapy.
  • Currently receiving any other investigational agents.
  • Received chemotherapy, or undergone major surgery within the prior 2 weeks and radiotherapy within the last 24 hours.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to (study agent) or other agents used in study.
  • Symptomatic brain metastases will be excluded from trial secondary to poor prognosis. However, individuals who have had treatment for their brain metastasis and whose brain disease is stable without steroid therapy for 1 week or on physiologic doses of steroids may be enrolled.
  • Requirement for any medications or substances that are strong inhibitors or inducers of CYP3A during the course of the study are ineligible.
  • Evidence of severe or uncontrolled systemic disease, or any concurrent condition, which could compromise participation in the study, including, but not limited to, active or uncontrolled infection, immune deficiencies, Hepatitis B, Hepatitis C, uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia, stroke/cerebrovascular accident within the past 6 months, or psychiatric illness/social situations which would jeopardize compliance with the protocol.
  • HIV-positive on or off combination antiretroviral therapy are ineligible.
  • Pregnant women are excluded from this study.

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): NCT04802174


Contacts
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Contact: Rasa Vilimas, R.N. (240) 858-3158 rasa.vilimas@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Anish Thomas, M.D. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04802174    
Other Study ID Numbers: 10000176
000176-C
First Posted: March 17, 2021    Key Record Dates
Last Update Posted: December 7, 2021
Last Verified: December 1, 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
SCLC
HGNC
M6620
Additional relevant MeSH terms:
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Carcinoma, Neuroendocrine
Carcinoma, Small Cell
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue