Biomarker Directed Trial of Temozolomide and PARP Inhibition in Relapsed SCLC

Randomized phase 2, multicenter, biomarker directed clinical trial to assess the efficacy of PARP inhibitor plus Temozolomide (TMZ) in relapsed Small Cell Lung Cancer patients. This study will explore if the biomarkers the investigators test predict sensitivity to the combination of PARP inhibitor plus TMZ and therefore leads to a better treatment response. There are two potential tests of biomarkers that can predict who would benefit from the oral combination of PARP inhibitor with Temozolomide (TMZ), but they have not been evaluated. This study will test for this sensitivity using a biomarker (found in the blood that may be related to how a person reacts to a drug). Participants will be assigned to one of the two groups. Group 1 will be patients that test negative for the biomarker and will receive treatment with Lurbinectedin as per standard of care guidelines. Group 2 will be patients that test positive for the biomarker that will be randomly assigned to either the combination of Niraparib plus Temozolomide (TMZ) or Lurbinectedin.

Randomized phase 2, multicenter, clinical trial to assess the efficacy of PARP inhibitor plus Temozolomide (TMZ) in biomarker selected relapsed SCLC patients. The investigators will test for sensitivity of two biomarkers in the blood SLFN11 and MGMT. Biomarker-positive (sensitive) patients are randomized 2:1 to either experimental Arm 2 (PARP inhibitor 200mg + 40mg TMZ oral daily for 21 days or 3.2mg/m2 Lurbinectedin IV infusion over one-hour every 21 days.). This requires 101 sensitive patients (67 on combination drug and 34 on Lurbinectedin). Biomarker-negative (resistant) patients will be enrolled on the control Arm 1 standard of care 3.2mg/m2 Lurbinectedin IV infusion over one-hour every 21 days. This requires 51 resistant patients on the control arm. The investigators will determine if biomarker (positive) sensitive patients will benefit from the oral combination PARP inhibitor + TMZ.

Eligibility Criteria:
Inclusion Criteria:

* Age 18 years or older at the time of consent.
* Histological or cytological diagnosis of extensive-stage small cell lung cancer.
* Patients must have received one prior line of systemic therapy.

  * Patients must have received first-line therapy with Carboplatin and Etoposide.

    * If patient is re-treated with Carboplatin and Etoposide at least 6 months or more after first regimen, this will still be considered one line of
    * treatment and they will qualify for this trial.
  * Patients could have received immunotherapy in combination with the chemotherapy regimen.
  * Patients who have received Tarlatamab as second line treatment are allowed.
* ECOG Performance status 0-2.
* Measurable disease as per RECIST v1.1 (NOTE: Previously irradiated lesions are eligible as a target lesion only if there is documented progression of the lesion after irradiation).
* Adequate bone marrow, liver, and renal function, as assessed by the following laboratory requirements:

  * ANC 1.5
  * Platelets 100 × 109/L
  * Hemoglobin 9 g/dL or 5.6 mmol/L
  * Aspartate transaminase and alanine transaminase 2.5 × upper limit of normal (ULN), \<5× in patients with known liver metastases
  * Serum total bilirubin 1.5 × ULN, 1.5-3.0 × ULN may be included appropriate starting dose adjustment to 200 mg daily.
  * Creatinine \<1.5 × ULN or estimated glomerular filtration rate (GFR) 50 ml/min by Cockcroft-Gault. Depending on scenario, GFR 30-49 can be --permissible.
* Women of child-bearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test within 72 hours of cycle 1 Day 1.
* Male and female subjects of child-bearing potential must agree to use a double-barrier method of birth control from the screening visit through 180 days after the last dose of study drug.
* Male subjects of child-bearing potential must agree to use a double-barrier method of birth control including use a male condom (and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak) and must agree to refrain from donating sperm from screening visit through at least 90 days after the last dose of study drug.
* Previously treated or asymptomatic brain metastases are allowed.

Exclusion Criteria:

* Unstable or clinically significant concurrent medical condition, psychiatric illness or social situation that would, in the opinion of the investigator, jeopardize the safety of a subject and/or their compliance with the protocol.
* Clinically significant acute infection requiring systemic antibacterial, antifungal, or antiviral therapy. (Suppressive therapy for chronic infections allowed, for example: Subjects with HIV/AIDS with adequate antiviral therapy to control viral load would be allowed. Subjects with viral hepatitis with controlled viral load would be allowed while on suppressive antiviral therapy.)
* Prior exposure to lurbinectedin, TMZ or niraparib.
* Pregnant or breastfeeding.
* Subject with known hypersensitivity to niraparib components or excipients including tartrazine 9yellow #5) or any other study products are excluded.
* Subject with known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) are excluded.
* Participants have systolic BP \>140 mmHg or diastolic BP \>90 mmHg that has not been adequately treated or controlled.
* Any patient with prior history of Posterior Reversible Encephalopathy Syndrome (PRES).