A Multicenter Phase II Trial to Evaluate Rechallenge With Platinum-based Chemotherapy (Carboplatin, Etoposide) for Progression During Tarlatamab Therapy in Relapsed Extensive Disease Small-cell Lung Cancer (SCLC)

Starting soon · Phase 2

Conditions studied: Extensive Disease Small Cell Lung Cancer

In brief

The integration of tarlatamab, a bispecific T-cell engager molecule targeting both DLL3 and CD3, into the treatment algorithm for SCLC will substantially improve the prognosis of patients. Nevertheless, disease progression will inevitably occur. Major challenges for further improving tarlatamab therapy are the molecular understanding of resistance to tarlatamab and the selection of the optimal systemic therapy upon progression. Patients who experience platinum-sensitive progression more than 90 days after first-line chemoimmunotherapy (platinum-free interval (PFI) = day of last administration of platinum-containing chemotherapy until progression) and subsequently progress on tarlatamab therapy may benefit from a platinum-based chemotherapy re-challenge while remaining on tarlatamab treatment. We hypothesize that patients who progress while on tarlatamab may benefit more from the combination of both therapies than from sequential therapy due to synergistic effects. We assume that, besides the cytotoxic effects of platinumbased chemotherapy, additional T-cell modifying effects could support this concept. The disruption of the tumor stroma, which has been described in various chemotherapies, could increase T-cell infiltration and thus have additional immunostimulatory effects (Hoff et al., 2011). The lymphodepletion triggered by chemotherapy and the resulting release of interleukins such as IL-15 could also have an enhancing effect on therapy with bispecific T-cell engagers (Kochenderfer et al., 2017). In addition, it has been shown preclinically that chemotherapeutic agents that have an inhibitory effect on topoisomerase (e.g. doxorubicin) also have a selective inhibitory effect on MDSCs. Here, the administration of the topoisomerase inhibitor etoposide could counteract possible resistance mechanisms (Alizadeh et al., 2014). Different cut-off values for chemotherapy-sensitive progression in small cell lung cancer between 60 - 90 days PFI have been discussed for decades. It has been shown that a platinum re-challenge as a second chemotherapy regimen is superior in a patient population with a PFI greater than 90 days compared to topotecan (Baize et al., 2020). This is expected to apply to approximately 40% of patients receiving standard first-line platinum-based therapy with PD-L1 inhibitors (Torsawa et al., 2023). If tarlatamab is added to first-line therapy in the near future, the proportion of patients with a PFI of more than 90 days could increase further. In the future, platinum-containing chemotherapy could become an increasingly important role as second-line chemotherapy. In parallel with the clinical evaluation of the re-challenge concept, we will conduct an extensive rebiopsy program. This will include a re-biopsy during progression to tarlatamab therapy at screening and a re-biopsy at the time of progression to the study treatment. Whole exome sequencing and transcriptomic analyses of tumor bulks as well as transcriptomic analysis at the single-cell level will be performed to elucidate molecular mechanisms of resistance in the tumor cells and in the tumor microenvironment. Additional immunohistochemical

Key facts

Study ID

NCT07699237

Run by

University of Cologne

People needed

54

Starts

2026-11-01

Expected to finish

2031-06-30

Last updated by the study team

2026-07-13

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• Capable of providing signed informed consent, which includes compliance with the requirements and restrictions outlined in the informed consent form (ICF) and this protocol. Written informed consent and any locally required authorization (e.g., European Union [EU] Data Privacy Directive) must be obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
• Provision of signed and dated, written ICF prior to any mandatory study-specific procedures, sampling, and analyses.
• Age ≥ 18 years at the time of signing the informed consent.
• Willing and able to comply with the protocol for the duration of the study including treatment and scheduled visits, examinations, and follow-up.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
• Patients must have a life expectancy of ≥ 12 weeks.
• Histologically or cytologically confirmed locally advanced or metastatic SCLC (UICC stage III not amenable to curative radiochemotherapy or stage IV). Note: Assignment of stage must be done according to the 9th edition of American Joint Committee on Cancer (AJCC)/Union for Interational Cancer Control (UICC) TNM staging system
• Disease progression or relapse after first-line platinum-based therapy with a platinum-free interval (PFI) ≥ 90 days (time between last platinum administration and first documented progression).
• Patients who received first-line systemic platinum-based chemotherapy for extensive stage (ES) disease are eligible.
• Patients must have failed or be ineligible for PD-L1 inhibitor therapy.
• Only one prior line of systemic chemotherapy is permitted. Patients who have previously been treated with chemotherapy as part of a limited stage (LS) disease may participate if there was a period of >6 months between the end of chemotherapy during the LS disease and chemotherapy as part of the ES disease.
• Radiological evidence of disease progression while on treatment with tarlatamab. Patients who show progression on tarlatamab in combination with a PD-L1 inhibitor may be included.
• Before starting study therapy (C1D1), a new biopsy of the tumor must be performed after progression under tarlatamab.
• Lesions that show progression under tarlatmab should be prioritized. Appropriate documentation (e.g., radiological report) must be available to demonstrate progress under Tarlatamab.
• Patients must be eligible for a biopsy of the tumor tissue in accordance with the guidelines of the treating institution.
• The tumor sample must be provided to the sponsor in accordance with the provisions of this protocol. The shipment should be made as soon as possible.
• If a tumor sample has already been taken after progression under tarlatmab for other reasons, the archived material can also be used for inclusion, and no new tumor biopsy is required for study inclusion.
• If a biopsy is not possible during tarlatamab treatment and no archived tumor sample is available after progression under tarlatamab, inclusion may be possible after discussion with the sponsor.
• Availability of a tumor sample obtained prior to the start of first-line treatment.
• The tumor sample must be provided to the sponsor in accordance with the provisions of this protocol. The tumor sample should have been sent to the sponsor prior to C1D1.
• If unavailable, inclusion may be possible after discussion with the sponsor.
• There must be a maximum of 28 days between the last dose of tarlatamab and the first dose of tarlatamab as part of the study treatment. Patients may receive tarlatamab beyond progression as standard therapy during the screening phase. If tarlatamab was last administered with a PD-L1 inhibitor, this therapy may be continued during screening as part of standard of care. No PD-L1 inhibitor may be administered after C1D1.
• Adequate tumor imaging (CT or MRI) within 28 days prior to enrollment. Imaging from the standard of care can be used for inclusion. For adequate imaging a slice thickness of 5 mm in CT and 5 mm in MRI with contrast agent should not be exceeded. More detailed information can be found in the Radiology Manual.
• Measurable disease as defined per RECIST 1.1 within the 28-day screening period.
• Adequate hematologic and organ function:

You may not qualify if…

• Symptomatic CNS metastases. Subjects with treated or untreated brain metastases are eligible provided the following criteria are met:
• Subject is asymptomatic from brain metastases. If, in the opinion of the investigator, asymptomatic, untreated brain metastases do not require local therapy, patients may be included.
• Whole brain radiation or surgery was completed at least 2 weeks prior to first dose of study treatment
• Stereotactic radiosurgery completed at least 7 days prior to first dose of study treatment
• Any CNS disease is clinically stable, subject is off steroids for CNS disease for at least 5 days (unless steroids are indicated for a reason unrelated to CNS disase), and subject is off or on stable doses of anti epileptic drugs at least 14 days prior to first dose of study treatment
• History of leptomeningeal carcinomatosis.
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
• Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy. Exceptions are:
• Alopecia (any Grade)
• Vitiligo (any Grade)
• Dysgeusia (any Grade)
• Hypothyroidism stable on hormone replacement (Grade ≤2)
• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the sponsor
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment may be included only after consultation with the sponsor.
• For special requirements in the laboratory see Point 14 at inclusion criteria. Note: Grading of toxicities must be done according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.
• History of another primary malignancy in the past 2 years. Exceptions are:
• Malignancy treated with curative intent and with no known active disease >1 years before the first dose of study treatment and of low potential risk for recurrence
• Adequately treated non melanoma skin cancer or lentigo maligna without evidence of disease
• Adequately treated carcinoma in situ without evidence of disease
• Curatively treated localized prostate cancer receiving androgen deprivation therapy and considered to have a very low risk of recurrence
• Lobular carcinoma in situ or ductal carcinoma in situ of the breast that is considered completely cured
• Curatively treated in situ cancer of the cervix, ductal carcinoma in situ, Stage 1, grade 1 endometrial carcinoma
• Curatively treated localized breast cancer receiving antihormonal agents and considered to have a very low risk of recurrence.
• Any acute, chronic or uncontrolled medical, mental or psychological condition, which in the opinion of the investigator would not permit the subject to participate in the study, complete the study or understand the patient information. These may include, but are not limited to:
• Uncontrolled infection

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