M7824 + Chemotherapy for Small Cell Lung Cancer

Overseen By Danielle F Pinkiert, R.N.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Live vaccines

Disqualifiers: Symptomatic brain metastases, Uncontrolled diabetes, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

Duration: Until disease progression or protocol criteria met

37 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

BACKGROUND: * Small cell lung cancer (SCLC) is an aggressive cancer with a poor prognosis. Although highly responsive to chemotherapy initially, SCLC relapses quickly and becomes refractory to treatment within a few months. * The inability to destroy residual SCLC cells despite initial chemosensitivity suggests the existence of a highly effective deoxyribonucleic acid (DNA) damage response network. SCLC is also characterized by high DNA replication stress (retinoblastoma (RB1) inactivation, MYC and CCNE1 activation). * There is only one Food and Drug Administration (FDA) approved treatment for patients with relapsed SCLC after first-line chemotherapy: topotecan, which inhibits religation of topoisomerase I-mediated single-strand DNA breaks leading to lethal double-strand DNA breaks. Temozolomide, an oral alkylating agent, which causes DNA damage by alkylating guanine at position O6 also has activity in relapsed SCLC, particularly for brain metastases. * Preliminary evidence indicates that disruption of the immune checkpoint programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway can yield responses in a subset of SCLC patients, but response rates (approximately equal to 10%) are lower than non-small cell lung cancer (NSCLC) and other tumors with comparable tumor mutational burden indicating additional immunosuppressive mechanisms at play in the SCLC tumor microenvironment. * M7824 (MSB0011359C) is a bifunctional fusion protein consisting of an anti-programmed death ligand 1 (PDL1) antibody and the extracellular domain of transforming growth factor beta (TGF-beta) receptor type 2, a TGF-beta trap. * Safety data from the dose-escalation study in solid tumors as well as preliminary data from expansion cohorts show that M7824 has a safety profile similar to other checkpoint inhibiting compounds. * Combining immunotherapy, and chemotherapy could synergistically improve the anticancer activity of immunotherapy. Combination of chemotherapy with immunotherapy have improved outcomes in NSCLC and melanoma leading to Food and Drug Administration (FDA) approvals of such combinations. * We hypothesize that increased DNA damage induced by topotecan and temozolomide will complement the anti-tumor activity of M7824, in recurrent SCLC. OBJECTIVE: - The primary objective of the trial is to determine the efficacy (using objective response rate) of M7824 plus topotecan or temozolomide in relapsed SCLC. ELIGIBILITY: * Subjects with histological or cytological confirmation of SCLC. * Subjects must be greater than or equal to 18 years of age and have a performance status (Eastern Cooperative Oncology Group (ECOG) less than or equal to 2. * Subjects must not have received chemotherapy or undergone major surgery within 2 weeks and radiotherapy within 24 hours prior to enrollment. * Subjects must have adequate organ function and measurable disease. DESIGN: * Arm A (M7824 monotherapy): Up to 10 patients may be treated with M7824 monotherapy to obtain safety and pharmacokinetic (PK) data, and a preliminary estimate of clinical responses to M7824 in SCLC. Patients with progressive disease on Arm A may then receive M7824 plus temozolomide as per description of treatment for Arm C. * Arm B (M7824 plus topotecan) and Arm C (M7824 plus temozolomide) will be administered in 3 and 4-week cycles respectively; these arms will have a safety run-in followed by efficacy analysis. Up to 10 patients with extrapulmonary small cell cancer will be enrolled in arm C to receive the combination of M7824 and temozolomide. * Optional tumor biopsies will be obtained at pre-treatment on cycle 1 day 1 (C1D1) and C1D15 for Arm C; pre-treatment on C1D1 and cycle 2 day 1 (C2D1) for arms A and B. * Every subject of each arm of the safety run-in will be observed for at least 7 days after first dose of M7824 before the subsequent subject can be treated. Subjects who are not evaluable for dose-limiting toxicity (DLT) will be replaced and not included into evaluation. ARMS: * Arm A (3-week cycles): M7824 monotherapy 2400 mg every 3 weeks until disease progression or a criterion in Protocol is met. Patients with progressive disease on Arm A may then receive 1200 mg M7824 every 2 weeks plus temozolomide 200 mg/m\^2/day on days 1-5 every 4 weeks. * Arm B (3-week cycles): M7824 2400 mg plus topotecan 1 mg/m(2) on days 1-5 every 3 weeks until disease progression or a criterion in Protocol is met. * Arm C (4-week cycles): M7824 1200 mg every 2 weeks plus temozolomide 200 mg/m(2)/day on days 1-5 every 4 weeks until disease progression or a criterion in Protocol is met.

Do I have to stop taking my current medications to join the trial?

The trial protocol does not specify if you must stop taking your current medications. However, you must not have received chemotherapy or undergone major surgery within 2 weeks, and radiotherapy within 24 hours prior to enrollment. You also cannot be on any other investigational agents. It's best to discuss your current medications with the trial team to ensure eligibility.

What safety data exists for M7824 + chemotherapy in small cell lung cancer?

The safety data for temozolomide, a component of the treatment, indicates it has a good safety profile with nonoverlapping toxicities and is generally well-tolerated. Common side effects include fatigue, nausea, vomiting, thrombocytopenia, and neutropenia, while severe myelosuppression is uncommon. Rare cases of severe hematological effects like aplastic anemia have been reported. The combination of temozolomide with other agents like carmustine and irinotecan has shown additive or synergistic effects with manageable toxicity levels. However, specific safety data for M7824 (Bintrafusp alfa) combined with chemotherapy in small cell lung cancer is not detailed in the provided research. ^{1 2 3 4 5}

Is the drug M7824, Temozolomide, Topotecan a promising treatment for small cell lung cancer?

Yes, the drug combination of M7824, Temozolomide, and Topotecan shows promise for treating small cell lung cancer. Research indicates that these drugs can be effective, especially in patients who have relapsed or have not responded to other treatments. Temozolomide, in particular, has shown potential when combined with other drugs, and Topotecan has been active in treating this type of cancer. These findings suggest that this drug combination could be a valuable option for patients. ^{6 7 8 9 10}

What data supports the idea that M7824 + Chemotherapy for Small Cell Lung Cancer is an effective treatment?

The available research does not provide specific data on the effectiveness of M7824 combined with chemotherapy for small cell lung cancer. Instead, it discusses other treatments like temozolomide with olaparib and topotecan with ifosfamide or etoposide. These studies suggest that while there are some promising combinations for treating small cell lung cancer, there is no direct evidence from the provided information about the effectiveness of M7824 with chemotherapy for this condition. ^{7 9 11 12 13}

Who Is on the Research Team?

Anish Thomas, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

This trial is for adults over 18 with relapsed Small Cell Lung Cancer (SCLC) who've had at least one chemotherapy treatment and whose cancer has progressed after immunotherapy. They should not have had chemo, major surgery within the last 2 weeks, or radiotherapy in the past 24 hours. Participants need to be physically capable of undergoing treatment (ECOG ≤2), have measurable disease, and proper organ function.

Inclusion Criteria

Subjects must have measurable disease per RECIST 1.1

My cancer is confirmed as small cell lung cancer or related type.

Ability of subject to understand and the willingness to sign a written informed consent document

Exclusion Criteria

I have not received any live vaccines in the last 30 days.

My tumor can potentially be cured according to my doctor.

I have brain metastases that are causing symptoms.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Run-In

Initial safety assessment of M7824 monotherapy and combination therapies with topotecan or temozolomide

3-4 weeks

1 visit (in-person) per cycle

Treatment

Participants receive M7824 monotherapy or combination therapy with topotecan or temozolomide in 3 or 4-week cycles

Until disease progression or protocol criteria met

1 visit (in-person) per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• M7824
• Temozolomide
• Topotecan

Trial Overview The study tests M7824 alone or combined with Topotecan or Temozolomide in patients with SCLC that's come back after previous treatments. It aims to see if adding M7824 to standard drugs can better control cancer growth. Patients are divided into three groups: one receives only M7824; another gets M7824 plus Topotecan; and the third takes M7824 with Temozolomide.

How Is the Trial Designed?

Group I: Arm C/M7824 (MSB0011359C) Plus Temozolomide Experimental Treatment 10 Interventions

M7824 (MSB0011359C) intravenous (IV) days 1 and 15 plus temozolomide (oral) on days 1-5 of a 28-day cycle. At least 6 subjects with small cell lung cancer (SCLC) to receive M7824 plus temozolomide to determine safety. 4 more SCLC patients enrolled at initial or lower dose for efficacy. If efficacious, an additional 12 SCLC subjects enrolled. After the 6 safety SCLC cohort, subjects with extrapulmonary small cell cancers will be enrolled.

Group II: Arm B/M7824 (MSB0011359C) Plus Topotecan Experimental Treatment 10 Interventions

M7824 (MSB0011359C) intravenous (IV) on day 1 plus topotecan (IV) on days 1-5 of a 21-day cycle. At least 6 subjects to receive M7824 plus topotecan to determine safety. 4 more patients enrolled at initial or lower dose for efficacy. If efficacious, an additional 12 subjects enrolled.

Group III: Arm A/M7824 (MSB0011359C) Monotherapy Experimental Treatment 10 Interventions

M7824 (MSB0011359C) intravenous (IV) monotherapy once every 21 days on a 21-day cycle. If patients have progressive disease on arm A, they may receive combination therapy of M7824 and Temozolomide.

M7824 is already approved in United States, European Union for the following indications:

Approved in United States as Bintrafusp alfa for:

• Biliary tract cancer

Approved in European Union as Bintrafusp alfa for:

• No approved indications listed; under investigation for various cancers

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Temozolomide combined with olaparib shows promise as a treatment option for patients with small-cell lung cancer who have progressive disease after standard etoposide and platinum-based therapy.

The study emphasizes the use of co-clinical trials with patient-derived xenografts to enhance biomarker discovery, potentially leading to more personalized and effective treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide plus PARP Inhibition in Small-Cell Lung Cancer: Could Patient-Derived Xenografts Accelerate Discovery of Biomarker Candidates? Pacheco, JM., Byers, LA.[2019]

In a phase-I trial involving 12 heavily pretreated patients with advanced solid tumors, the combination of topotecan and ifosfamide was found to have a maximum tolerable dose (MTD) of 1.0 mg/m² of topotecan and 750 mg/m² of ifosfamide, but resulted in significant non-hematologic toxicities, including severe liver and renal issues in some patients.

Despite the combination showing potential in preclinical models, no clinical remissions were observed in the 11 evaluable patients, indicating that while the drugs can be combined, their efficacy in this setting remains questionable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I clinical and pharmacokinetic study of combination chemotherapy with topotecan and ifosfamide in patients with progressive or relapsed solid tumors. Schneider, CP., Merkel, U., Grübner, U., et al.[2013]

Topotecan is an effective topoisomerase I-targeting anticancer drug approved by the FDA for advanced ovarian cancer, providing a treatment option for patients who have progressed after platinum-based chemotherapy.

It shows promise in treating other cancers, such as small-cell lung cancer and pediatric tumors, and is being studied in combination with other therapies to potentially improve survival rates and cure outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical status and optimal use of topotecan. Takimoto, CH., Arbuck, SG.[2013]

In a study of 23 patients with relapsed or refractory small-cell lung cancer, the combination of topotecan and etoposide showed a modest overall response rate of 17.4%, with a median progression-free survival of 4.7 months and median overall survival of 9.5 months.

The treatment was associated with significant toxicities, including severe myelosuppression, with 78.3% of patients experiencing grade 3/4 neutropenia, indicating that while the regimen has some efficacy, it also carries considerable risks that need to be managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of topotecan and etoposide as a salvage treatment for patients with recurrent small cell lung cancer following irinotecan and platinum first-line chemotherapy. Choi, HJ., Cho, BC., Shin, SJ., et al.[2018]

In a phase I/II trial involving 52 pretreated patients with ovarian cancer, small-cell lung cancer, and non-small-cell lung cancer, the combination of topotecan and paclitaxel was found to be well-tolerated at maximum tolerated doses of 1.75 mg/m2 and 70 mg/m2, respectively.

The treatment resulted in a response rate of 33%, with one complete response and 16 partial responses, indicating preliminary efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Weekly administration of topotecan and paclitaxel in pretreated advanced cancer patients: a phase I/II study. Stathopoulos, GP., Rigatos, SK., Christodoulou, C., et al.[2015]

Temozolomide is a promising drug for combination therapies due to its ability to cross the blood-brain barrier, good safety profile, and effectiveness against solid tumors like malignant glioma, especially when combined with carmustine or irinotecan.

Studies indicate that administering carmustine before temozolomide results in lower toxicity and a higher maximum tolerated dose, while the combination of temozolomide followed by irinotecan shows greater effectiveness than either drug alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in combination with other cytotoxic agents. Prados, M.[2019]

The TMZ-resistant glioma cell line SF188/TR showed a 6-fold resistance to temozolomide and cross-resistance to various other anticancer agents, indicating a significant challenge in treating resistant tumors.

Increased activity of the enzyme alkylguanine alkyltransferase (AGT) was identified as a primary mechanism of resistance to TMZ, while changes in the balance of pro-apoptotic and anti-apoptotic proteins contributed to broader cross-resistance to other drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biochemical changes associated with a multidrug-resistant phenotype of a human glioma cell line with temozolomide-acquired resistance. Ma, J., Murphy, M., O'Dwyer, PJ., et al.[2022]

A new method was developed to measure the levels of the active metabolite MTIC in the plasma of patients receiving temozolomide (TMZ), which is crucial for understanding its antitumor activity.

In a study of 15 patients, MTIC was found to peak in plasma about 1 hour after TMZ administration, with a half-life of 88 minutes, indicating that it does not accumulate in the body after multiple doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of 3-methyl-(triazen-1-yl)imidazole-4-carboximide following administration of temozolomide to patients with advanced cancer. Reid, JM., Stevens, DC., Rubin, J., et al.[2018]

The study confirmed that the generic temozolomide capsules (TOZ039) are bioequivalent to the brand Temodal® capsules, with pharmacokinetic parameters falling within the acceptable range for both 20-mg and 100-mg doses in 29 patients with brain tumors.

The treatment was found to be safe, with no treatment-related severe adverse events or mortality reported, although 82.8% of patients experienced some adverse effects, highlighting the importance of monitoring patient responses during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioequivalence study of 20-mg and 100-mg temozolomide capsules (TOZ309 and Temodal®) in glioma patients in China. Hu, C., Lin, Q., Liu, C., et al.[2021]

Temozolomide (TMZ) is generally safe with mild to moderate side effects, but this case report highlights a rare instance of severe aplastic anemia (AA) in a 68-year-old female patient following treatment for glioblastoma, indicating a potential serious risk associated with the drug.

The patient's AA was managed successfully with supportive care, including platelet transfusions and growth factor treatment, and her blood counts returned to normal within 38 days, emphasizing the importance of monitoring blood parameters during and after TMZ treatment to detect such rare toxicities early.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide-induced aplastic anaemia: Case report and review of the literature. Gilbar, PJ., Pokharel, K., Mangos, HM.[2022]

Topotecan combined with either cisplatin or etoposide showed similar efficacy in treating untreated extensive disease small-cell lung cancer (ED SCLC), with response rates of 63.4% for the T/C group and 61.0% for the T/E group, indicating both combinations are effective treatment options.

While both regimens had similar overall deliverability, the T/C combination resulted in significantly higher rates of severe anemia (46.4%) compared to T/E (20%), suggesting that T/E may have a better safety profile regarding hematological toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomised phase II study of the efficacy and safety of intravenous topotecan in combination with either cisplatin or etoposide in patients with untreated extensive disease small-cell lung cancer. Quoix, E., Breton, JL., Gervais, R., et al.[2013]

In a phase II study involving 64 patients with relapsed small cell lung cancer (SCLC), temozolomide demonstrated an overall response rate of 23% in patients with sensitive disease and 13% in those with refractory disease, indicating its potential efficacy as a treatment option.

The study found that patients with methylated MGMT had a significantly higher response rate to temozolomide (38%) compared to those with unmethylated MGMT (7%), suggesting that MGMT methylation status may be a useful biomarker for predicting treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of temozolomide in patients with relapsed sensitive or refractory small cell lung cancer, with assessment of methylguanine-DNA methyltransferase as a potential biomarker. Pietanza, MC., Kadota, K., Huberman, K., et al.[2018]

The combination of olaparib and temozolomide showed a promising overall response rate of 41.7% in a phase I/II trial involving 50 patients with previously treated small-cell lung cancer (SCLC), indicating its potential as an effective treatment option.

A molecular signature was identified that correlates low expression of inflammatory-response genes with resistance to the treatment, helping to predict which tumors are more likely to respond to the olaparib/temozolomide combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination Olaparib and Temozolomide in Relapsed Small-Cell Lung Cancer. Farago, AF., Yeap, BY., Stanzione, M., et al.[2020]

Citations

1. United States pubmed.ncbi.nlm.nih.gov

Temozolomide plus PARP Inhibition in Small-Cell Lung Cancer: Could Patient-Derived Xenografts Accelerate Discovery of Biomarker Candidates? [2019]

2. Germany pubmed.ncbi.nlm.nih.gov

Phase I clinical and pharmacokinetic study of combination chemotherapy with topotecan and ifosfamide in patients with progressive or relapsed solid tumors. [2013]

3. United States pubmed.ncbi.nlm.nih.gov

Clinical status and optimal use of topotecan. [2013]

4. Germany pubmed.ncbi.nlm.nih.gov

Combination of topotecan and etoposide as a salvage treatment for patients with recurrent small cell lung cancer following irinotecan and platinum first-line chemotherapy. [2018]

5. Germany pubmed.ncbi.nlm.nih.gov

Weekly administration of topotecan and paclitaxel in pretreated advanced cancer patients: a phase I/II study. [2015]

6. United States pubmed.ncbi.nlm.nih.gov

Temozolomide in combination with other cytotoxic agents. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Biochemical changes associated with a multidrug-resistant phenotype of a human glioma cell line with temozolomide-acquired resistance. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of 3-methyl-(triazen-1-yl)imidazole-4-carboximide following administration of temozolomide to patients with advanced cancer. [2018]

9. Germany pubmed.ncbi.nlm.nih.gov

Bioequivalence study of 20-mg and 100-mg temozolomide capsules (TOZ309 and Temodal®) in glioma patients in China. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Temozolomide-induced aplastic anaemia: Case report and review of the literature. [2022]

11. Ireland pubmed.ncbi.nlm.nih.gov

A randomised phase II study of the efficacy and safety of intravenous topotecan in combination with either cisplatin or etoposide in patients with untreated extensive disease small-cell lung cancer. [2013]

12. United States pubmed.ncbi.nlm.nih.gov

Phase II trial of temozolomide in patients with relapsed sensitive or refractory small cell lung cancer, with assessment of methylguanine-DNA methyltransferase as a potential biomarker. [2018]

13. United States pubmed.ncbi.nlm.nih.gov

Combination Olaparib and Temozolomide in Relapsed Small-Cell Lung Cancer. [2020]