Background:

      Small cell lung cancer (SCLC) and high-grade neuroendocrine cancers (HGNEC) are aggressive
      neuroendocrine cancers with poor prognosis. Although responsive to chemotherapy initially,
      both tumor types relapse quickly and become refractory to treatment within a few months.

      Replication stress is an SCLC hallmark, driven by oncogenes that drive rapid and unscheduled
      proliferation (TP53 and RB1 inactivation, MYC amplification, etc.). HGNECs share similarities
      in morphology, biologic behavior with SCLC. Treatment paradigms have largely paralleled those
      established for SCLC.

      ATR is the master regulator of replication stress response. Upon activation, the ATR CHK1
      signaling leads to cell cycle arrest and promotes replication fork stabilization and restart.

      ATR inhibition generates replication stress and disables cell cycle checkpoints to ultimately
      cause mitotic catastrophe and cell death. Many genotoxic agents currently used in cancer
      therapy are also potent inducers of replication stress.

      Berzosertib is a potent and selective kinase inhibitor of ATR, with demonstrated safety and
      anti-tumor activity as monotherapy and combination with multiple chemotherapeutics (including
      platinum, gemcitabine, and topoisomerase inhibitors) in high replication stress tumors.

      Lurbinectedin is a recently approved second-line SCLC treatment which forms DNA adducts by
      covalently binding to the minor groove of DNA that kills cancer cells by inhibiting Pol-II
      and causing DNA damage

      We hypothesize that a combination of ATR kinase inhibition with lurbinectedin will provide an
      attractive synergistic therapeutic option for SCLC and HGNEC.

      Primary objectives:

      Phase I: To identify the maximum tolerated dose (MTD) of lurbinectedin in combination with
      berzosertib.

      Phase II: To assess the efficacy with respect to clinical response rate of a combination of
      lurbinectedin and berzosertib in previously treated participants with SCLC and HGNECs.

      Eligibility:

      All phases: Participants must be greater than or equal to 18 years of age and have a
      performance status (ECOG) less than or equal to 2. Participants must not have received
      chemotherapy or undergone major surgery within 2 weeks and radiotherapy within 24 hours prior
      to enrollment.

      Phase I: Participants with histologically confirmed solid tumors and progression on standard
      therapies. Participants with evaluable, but not measurable disease will be eligible for Phase
      I.

      Phase II: Participants with histological confirmation of SCLC or HGNEC. Participants must
      have measurable disease to be eligible for Phase II.

      Design:

      This is a Phase I/II, open label clinical trial identifying the maximum tolerated dose (MTD)
      of lurbinectedin in combination with berzosertib in a phase I trial, and assessing the
      efficacy with respect to clinical response rate of a combination of lurbinectedin and
      berzosertib as treatment of participants with recurrent SCLC and HGNEC. The accrual ceiling
      will be set to 75 for this study.

      Participants will receive lurbinectedin on day 1 and berzosertib on days 1 and 2,
      administered every 21 days (1 cycle), until disease progression or development of intolerable
      side effects.

      Blood, hair follicles, and tumor will be collected at various time points to support the
      exploratory objectives.

      Phase I will use a standard 3 + 3 design to determine MTD of the combination of lurbinectedin
      and berzosertib. With a maximum of three dose levels to be explored, there will be up to 18
      participants treated in phase I.