IMFORTE

Inclusion Criteria for Induction Phase

Participants must meet all of the following criteria to be eligible to enter the induction phase:

• Participants who are capable of giving signed informed consent and able to comply with the study protocol

• Participants who are age ≥ 18 years at the time of signing Informed Consent Form

• Participants who have ECOG Performance Status of 0 or 1

• Participants who have histologically or cytologically confirmed ES-SCLC (per the modified VALG staging system)

• No prior systemic treatment for ES-SCLC

• For participants who have received prior chemoradiotherapy for limited-stage SCLC: must have had treatment with curative intent and a treatment-free interval of at least 6 months between the last dose/cycle of chemotherapy, thoracic radiotherapy, or chemoradiotherapy and the diagnosis of ES-SCLC

• Participants must have adequate hematologic and end-organ function to receive 4 cycles of induction treatment with carboplatin, etoposide and atezolizumab

• Measurable disease, as defined by RECIST v1.1

– Previously irradiated lesions can only be considered as measurable disease if (1) disease progression has been unequivocally documented at that site since radiation therapy, (2) and the previously irradiated lesion is not the only site of measurable disease

• Submission of pre-induction therapy tumor sample for exploratory biomarker research

– A pre-induction therapy tumor tissue sample (archival or fresh biopsy) should be submitted as soon as possible following consent and no later than 4 weeks after enrollment; however, participants may be enrolled into the study before the pre-induction tumor tissue sample is submitted.

– Although any available tumor tissue sample (archival or fresh biopsy) can be submitted, it is strongly encouraged that representative tumor specimens in paraffin blocks (preferred) or 10 (or more) serial, freshly cut, unstained slides be submitted for exploratory biomarker analysis

• Participants who have a negative HIV test at screening, with the following exception: participants with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count ≥ 200/μL, and have an undetectable viral load

• Participants who have a negative hepatitis B surface antigen (HBsAg) test at screening

• Participants who have a negative total hepatitis B core antibody (HBcAb), or a positive total HBcAb test followed by a negative (per local laboratory definition) hepatitis B virus (HBV) DNA test at screening

– The HBV DNA test must be performed for individuals who have a negative HBsAg test, a negative HBsAb test, and a positive HBcAb test

• Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening

– The HCV RNA test must be performed for participants who have a positive HCV antibody test

• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use highly effective methods of contraception throughout the treatment period and for 5 months after the final dose of atezolizumab, and for 6 months after the final dose of carboplatin, etoposide, or lurbinectedin, whichever occurs last; agreement to refrain from donating eggs. Details further defined in the protocol.

– A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations.

– Examples of contraceptive methods with a failure rate of <1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.

– The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.

– Women who would like to become pregnant after study treatment discontinuation should seek advice on oocyte cryopreservation prior to initiation of study treatment because of the possibility of irreversible infertility due to treatment with carboplatin, etoposide and/or lurbinectedin.

• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating sperm, as defined below:

– With a female partner of childbearing potential who is not pregnant, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 4 months after the final dose of lurbinectedin, or for 6 months after the final dose of carboplatin or etoposide, whichever occurs last. Men must refrain from donating sperm during this same period.

– With a pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 4 months after the final dose of lurbinectedin, or for 6 months after the final dose of carboplatin or etoposide, whichever occurs last to avoid exposing the embryo.

– The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.

Inclusion Criteria for Maintenance Phase

Participants must meet all of the following criteria to be eligible to be randomized to receive either atezolizumab plus lurbinectedin or atezolizumab after completion of the induction phase:

• Participants who are able to comply with the study protocol

• Participants who have an ECOG Performance Status of 0 or 1

• Participants must have received 4 cycles of 1L treatment with carboplatin, etoposide and atezolizumab and must have an ongoing CR, PR, or SD by RECIST v1.1 after completion of the induction therapy

– Radiographic tumor assessment must have occurred ≤ 28 days prior to randomization

– Participants who have received < 4 cycles or > 4 cycles of carboplatin, etoposide and atezolizumab are not eligible

• Participants must be randomized within 5 weeks (35 days), from the day of the administration of the last dose of atezolizumab and/or platinum-based 1L chemotherapy (whichever occurs last). Participants receiving PCI must be randomized within 9 weeks (63 days) from the last dose of platinum-based 1L chemotherapy.

– Study treatment of the maintenance phase must not be administered < 3 weeks (21 days) from the last dose of atezolizumab and/or platinum-based 1L chemotherapy (whichever occurs last)

– Study treatment of the maintenance phase must not be administered < 2 weeks (14 days) from the last dose of radiotherapy

• All toxicities attributed to prior anti-cancer therapy must have been resolved to Grade ≤ 1 (according to NCI CTCAE v5.0) or baseline before administration of study treatment of the maintenance phase other than:

– Adverse events that are clinically non-significant and/or stable on supportive therapy in the opinion of the investigator, and are not expected to interfere with treatment in the study are eligible such as:

Grade ≤ 2 alopecia, asthenia, dermatologic events.

Grade ≤ 2 anemia if hemoglobin ≥ 90 g/L (9 g/dL).

Grade 2 (> 1.5−2.0 ×ULN) asymptomatic amylase and/or lipase elevation with no abdominal pain and no characteristic CT findings. However, weekly monitoring of amylase and lipase is required in this case.

• Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 7 days prior to initiation of study treatment of the maintenance phase:

– ANC ≥ 1.5 × 109/L (1500/μL) of non-African descendent or ANC ≥ 1.3 × 109/L (1300/μL) of African descent without G-CSF support

– Lymphocyte count ≥ 0.5 × 109/L (500/μL)

– Platelet count ≥ 100 × 109/L (100,000/μL) without transfusion

– Hemoglobin ≥ 90 g/L (9 g/dL)

Participants may be transfused to meet this criterion.

– AST, ALT, and ALP ≤ 2.5 × ULN, with the following exceptions:

Participants with documented liver metastases: AST and ALT ≤ 5 × ULN.

Participants with documented liver or bone metastases: ALP ≤ 5 × ULN.

– Total bilirubin ≤ 1.5 × ULN with the following exception:

Participants with known Gilbert disease: total bilirubin ≤ 3 × ULN.

– Creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 30 mL/min (calculated through use of the Cockcroft-Gault formula)

– Creatine phosphokinase (CPK) ≤ 2.5 × ULN (≤ 5.0 × ULN is acceptable if elevation is disease-related)

– Albumin ≥ 25 g/L (2.5 g/dL)

• For participants not receiving therapeutic anticoagulation: INR and aPTT ≤ 1.5 × ULN

• For participants receiving therapeutic anticoagulation: stable anticoagulant regimen. 

Exclusion Criteria for Induction Phase

Participants are excluded from enrollment in the study if any of the following criteria apply:

• Participants with CNS metastases

– A brain MRI scan with contrast is required at induction screening

• Participants who have spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for ≥ 1 week prior to randomization

• Participants who have Leptomeningeal disease

• Participants receiving cisplatin are not allowed during the induction phase

• Participants for whom consolidative chest radiation is planned are excluded

• Participants who have uncontrolled tumor-related pain

• Participants requiring pain medication must be on a stable regimen at study entry

• Participants with lesions (e.g., bone metastases or metastases causing nerve impingement) requiring palliative radiotherapy. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently).

– Participants with indwelling catheters (e.g., PleurX®) are allowed

• Participants who have uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL, or corrected calcium > ULN)

• Participants with known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, and inherited liver disease, or current alcohol abuse

• Participants with active or a history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, anti-phospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions:

– Participants with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study

– Participants with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study

– Participants with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., participants with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:

Rash must cover < 10% of body surface area.

Disease is well-controlled at baseline and requires only low-potency topical corticosteroids.

No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months.

• Participants with a history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan

– History of radiation pneumonitis in the radiation field (fibrosis) is permitted

• Participants with active tuberculosis

• Participants with significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina

– Participants with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate

• Participants with any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the participant at high risk from treatment complications

• Participants with a history of malignancies other than SCLC within 5 years prior to initiation of study treatment, with the exception of the cancer under investigation in this study and malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer

• Participants receiving current treatment with anti-viral therapy for HBV or HCV

• Participants receiving treatment with investigational therapy within 28 days prior to initiation of study treatment

• Participants who received prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti−CTLA-4, anti−PD-1, and anti−PD-L1 therapeutic antibodies

• Participants who received prior treatment with lurbinectedin or trabectedin

• Participants who received treatment with systemic immuno-stimulatory agents (including, but not limited to, interferon and interleukin [IL] 2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment

• Participants who have received treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−TNF-α agents) within 1 week prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions:

– Participants who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) may be eligible for the study after Medical Monitor confirmation has been obtained

– Participants who received mineralocorticoids (e.g., fludrocortisone), inhaled or low-dose corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study

• Participants with known allergy or hypersensitivity to any component of the lurbinectedin formulation

• Participants with a history of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins

• Participants with known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation

• Participants who received prior allogeneic stem cell or solid organ transplantation

• Participants who are pregnant or breastfeeding, or intending to become pregnant during study treatment or within 6 months after the final dose of study treatment

– Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment

Exclusion Criteria for Maintenance Phase

Participants are excluded from randomization in the study if any of the following criteria apply after completion of the induction phase:

• Participants with CNS metastases

– A brain MRI scan with contrast is required at maintenance screening and is the preferred modality for all subsequent scheduled follow-up tumor assessments

• Participants receiving consolidative chest radiation are excluded

• Participants with uncontrolled tumor-related pain

• Participants requiring pain medication must be on a stable regimen at entry of maintenance phase

• Participants with lesions (e.g., bone metastases or metastases causing nerve impingement) requiring palliative radiotherapy are not eligible

• Participants with uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL, or corrected calcium > ULN)

• Participants with a history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan

– History of radiation pneumonitis in the radiation field (fibrosis) is permitted

• Participants with active tuberculosis

• Participants who have undergone a major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment of the maintenance phase, or anticipation of need for a major surgical procedure during the study

• Participants with a severe infection within 2 weeks prior to initiation of study treatment in the maintenance phase, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that, in the opinion of the investigator, could impact participant safety

• Participants who received treatment with therapeutic oral or IV antibiotics at the time of randomization

– Participants receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or COPD exacerbation) are eligible for the study

• Participants with any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the participant at high risk from treatment complications

• Participants who have received treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment of the maintenance phase, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab. 

Research Nurse: Emma Davies  (01253 951679) Emma.davies16@nhs.net

Administrator: Arun Prakash