Study to Confirm Efficacy and Feasibility of Tarlatamab Treatment in Patients With Extensive Stage Small-cell Lung Cancer With Poor Performance Status

A Single-arm Phase II-study to Confirm Efficacy and Feasibility of Tarlatamab Treatment in Patients With Extensive Stage Small-cell Lung Cancer With Poor Performance Status

The SPACE-T study is a clinical trial for people with advanced small-cell lung cancer (SCLC) whose cancer has returned or spread despite previous treatment and whose general health is reduced (ECOG performance status 2). The study will include 57 participants at about 15 sites in Germany.

The study is testing tarlatamab, a treatment that helps the immune system recognize and attack cancer cells. Participants will receive tarlatamab through a vein, starting with a lower dose of 1 mg, followed by doses of 10 mg. Treatment will then generally be given every two weeks.

The main purpose of the study is to find out how effective tarlatamab is in this group of patients by assessing how many participants are alive 12 months after starting the study. The study will also examine how well the treatment controls the cancer, including cancer that has spread to the brain, how well participants tolerate the treatment, its side effects, and its impact on quality of life.

Patients with poorer general health are often not included in clinical trials, even though they represent an important part of the people treated for SCLC in everyday clinical practice. The SPACE-T study aims to provide more information about whether tarlatamab is effective and feasible for these patients.

The SPACE-T study is a phase II clinical trial investigating the treatment tarlatamab in people with advanced small-cell lung cancer (SCLC). The study focuses specifically on patients whose cancer has returned or spread after previous treatment and whose general health and ability to carry out everyday activities are reduced (ECOG performance status 2). This patient group is often underrepresented in clinical trials, although it represents an important part of patients treated for SCLC in routine clinical practice.

A total of 57 patients are planned to participate at approximately 15 study sites in Germany. To take part, patients must be at least 18 years old and have confirmed small-cell lung cancer that has returned or spread to other parts of the body. They must have received at least one previous treatment for recurrent or metastatic disease. In general, previous treatment should have included platinum-based chemotherapy, etoposide and a PD-L1 inhibitor. Patients must also have cancer that can be measured on imaging examinations.

Patients with brain metastases may also participate in the study. However, patients cannot take part if brain metastases are causing new or worsening neurological symptoms. There are also other eligibility requirements relating, for example, to blood counts, liver and kidney function, breathing problems and previous cancer treatments. Patients who have previously received a treatment targeting DLL3 cannot participate.

All participants in the study will receive tarlatamab; there is no placebo or comparison group. Tarlatamab is a type of immunotherapy designed to bring the body's T cells into contact with cancer cells that carry a protein called DLL3. This is intended to help the immune system recognize and attack the cancer cells.

Tarlatamab is given through a vein. To reduce the risks associated with starting treatment, patients first receive a lower dose of 1 mg on the first day of treatment. They then receive the full 10 mg dose one week later and again one week after that. Afterwards, tarlatamab is generally given every two weeks.

The main aim of the SPACE-T study is to determine how effective tarlatamab is in this patient population. The main measure used for this assessment is the proportion of patients who are alive 12 months after starting the study. Other assessments will look at how long patients live overall, how long the cancer remains under control, how many patients have a reduction in the size of their cancer, and how long it takes before another cancer treatment is needed. For patients with brain metastases, the study will also examine how well the treatment controls cancer in the brain.

Another important aim is to understand whether tarlatamab can be given safely and practically to patients whose general health is reduced. The study will therefore closely assess side effects and how well patients tolerate treatment. It will also evaluate patients' quality of life and symptoms using questionnaires completed by the patients themselves. In addition, the study will investigate whether palliative radiotherapy, for example for symptomatic cancer lesions, can be incorporated into treatment with tarlatamab.

Blood samples and, where available as part of routine care, tumor tissue samples will also be collected for research. These samples will be used to study changes in the immune system during treatment and to investigate whether early immune responses may be related to how well a patient's cancer responds to tarlatamab.

Tarlatamab can cause specific immune-related side effects. These include cytokine release syndrome (CRS), an inflammatory reaction caused by activation of the immune system, and neurological side effects such as immune effector cell-associated neurotoxicity syndrome (ICANS). One reason for conducting the SPACE-T study is to obtain more information about the feasibility, safety and effectiveness of tarlatamab in patients with poorer general health, for whom there is currently limited clinical evidence.

Overall, the SPACE-T study aims to determine whether tarlatamab is an effective and feasible treatment option for patients with advanced small-cell lung cancer and reduced performance status, a population that more closely reflects many patients seen in everyday clinical practice.

Inclusion Criteria:

1. Written informed consent obtained from the subject prior to performing any protocol-related procedures.
2. Age ≥ 18 years
3. ECOG performance status 2
4. Histologically confirmed small-cell lung cancer (initial mixed histology / combined SCLC permitted if re-biopsy of current progression shows SCLC)
5. Recurrent or metastatic disease. In case of local-only recurrence, availability of local treatment options must have been excluded
6. Has received at least one prior line of treatment in the recurrent or metastatic setting
7. Has received a prior treatment line with platinum, etoposide, and a PD-L1 antibody. Treatment with chemotherapy only is acceptable if the patient had a contraindication for CPI treatment
8. Measurable disease according to RECIST v1.1

Exclusion Criteria:

1. ECOG performance status 0, 1, 3 or 4

2. Life expectancy less than three months

3. Active brain metastases with unstable symptoms (new or progressive neurological symptoms within the last 3 weeks)

4. Bone marrow insufficiency:

   1. neutrophil count < 1.5/nl or
   2. hemoglobin <8 mg/dl or
   3. platelets <100/nl

5. Advanced liver disease:

   1. Subjects with pre-existing chronic liver disease:

      iii. Total bilirubin > 1.5xULN or iv. ALT or AST > 3xULN

   2. Subjects with no relevant prior chronic liver disease and elevated liver parameters due to liver metastases:

   v. Total bilirubin > 3xULN or vi. ALT or AST > 10xULN c. International normalized ratio (INR) > 2.0 and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≥ 1.5 x ULN, except for subjects undergoing new class anticoagulant therapy (eg, Apixaban, Rivaroxaban, Edoxaban) with stable dose for 2 weeks prior to enrollment

6. Advanced kidney disease:

   CKD-EPI GFR <20 ml/min/1.73m²

7. Heart failure with reduced ejection fraction (EF < 40%, assessed by echochardiography performed within 3 months prior to C1D1)

8. Hemodynamically significant pericardial effusion

9. Clinically significant pleural effusion (Clinically significant pleural effusions must be managed by drainage. Re-check within 3 days prior to initiation of treatment.)

10. Respiratory compromise leading to an unjustifiable risk in case of higher-grade CRS, in the judgment of the investigator (possible criteria leading to such judgment: oxygen support at rest >2l/min, active pneumonia or pneumonitis)

11. Prior DLL3-directed treatment

12. Prior systemic therapy (chemotherapy, CPI) within 14 days prior to first dose of study treatment

13. Previous treatment in the present study (does not include screening failure)

14. History of immune-mediated encephalitis

15. Concurrent malignancy other than SCLC requiring active treatment

16. HIV infection not on stable antiviral treatment

17. Women of childbearing potential or men with partners of childbearing potential who are not adhering to contraceptive measures

18. Female subjects of childbearing potential

    1. unwilling to use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 60 days after the last dose of tarlatamab
    2. who are breastfeeding or who plan to breastfeed while on study through 60 days after the last dose of tarlatamab
    3. planning to become pregnant or donate eggs while on study through 60 days after the last dose of tarlatamab
    4. with a positive pregnancy test at screening

19. Male subjects

    1. with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use contraception during treatment and for an additional 60 days after the last dose of tarlatamab
    2. with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment and for an additional 60 days after the last dose of tarlatamab
    3. unwilling to abstain from donating sperm during treatment and for an additional 60 days after the last dose of tarlatamab

20. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities [§ 40 Abs. 1 S. 3 Nr. 4 AMG].

21. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].