Iadademstat + Atezolizumab/Durvalumab for Small Cell Lung Cancer

Recruiting at 31 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must be taking: Platinum etoposide chemotherapy

Must not be taking: Antidepressants, Immunosuppressives

Disqualifiers: Autoimmune disease, Organ transplant, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 12

45 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I/II trial tests the safety, side effects, and best dose of iadademstat when given together with atezolizumab or durvalumab, and studies the effect of the combination in treating patients with small cell lung cancer that has spread outside of the lung in which it began or to other parts of the body (extensive stage) who initially received standard of care chemotherapy and immunotherapy. Iadademstat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as atezolizumab or durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Adding iadademstat to either atezolizumab or durvalumab may be able to stabilize cancer for longer than atezolizumab or durvalumab alone in treating patients with extensive stage small cell lung cancer.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as specific anti-depressants (tranylcypromine or phenelzine) and any immunosuppressive or immunostimulatory agents. Additionally, herbal and natural remedies, as well as complementary or alternative medicines, must be stopped at least one week before starting the study treatment.

What data supports the effectiveness of the drug combination Iadademstat + Atezolizumab/Durvalumab for Small Cell Lung Cancer?

Research shows that both atezolizumab and durvalumab, when combined with chemotherapy, improve overall survival in patients with extensive-stage small cell lung cancer compared to chemotherapy alone. This suggests that these drugs can be effective components in treating this type of cancer. ^{1 2 3 4 5}

Is the combination of Iadademstat with Atezolizumab or Durvalumab safe for humans?

Atezolizumab and Durvalumab, when combined with chemotherapy, have been generally well tolerated in patients with small cell lung cancer, with no new safety concerns beyond known side effects like rash and hypothyroidism (underactive thyroid). These treatments have been approved by the FDA based on trials showing they are safe and improve survival in this patient group. ^{5 6 7 8 9}

What makes the drug Iadademstat + Atezolizumab/Durvalumab unique for treating small cell lung cancer?

Iadademstat, combined with atezolizumab or durvalumab, is unique because it targets specific proteins to boost the immune system's ability to fight small cell lung cancer, potentially offering a new approach compared to traditional chemotherapy. ^{1 2 4 6 10}

Research Team

Charles Michael Rudin

Principal Investigator

JHU Sidney Kimmel Comprehensive Cancer Center LAO

Eligibility Criteria

This trial is for adults over 18 with small cell lung cancer that has spread and responded to initial chemo and immunotherapy. Participants must have a measurable tumor, weigh at least 50 kg, be able to swallow pills, and have an ECOG performance status of ≤2.

Inclusion Criteria

I can take pills by mouth.

My white blood cell count is healthy.

My lung cancer is confirmed to be small cell type.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Phase I Treatment

Patients receive iadademstat orally and continue receiving their initial ICI treatment. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle

4 visits (in-person) per cycle

Phase II Treatment

Patients are randomized to receive either iadademstat with ICI or ICI alone. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle

4 visits (in-person) per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up includes CT scans and blood and urine sample collection.

12 months

Every 3 months

Treatment Details

Interventions

• Atezolizumab
• Durvalumab
• Iadademstat

Trial Overview The trial tests the safety and optimal dose of Iadademstat combined with Atezolizumab or Durvalumab in patients with extensive stage small cell lung cancer. It aims to see if this combination can better control cancer than the standard treatments alone.

Participant Groups

Group I: Phase II, Arm I (iadademstat, atezolizumab, durvalumab) Experimental Treatment 9 Interventions

Patients in Phase II Arm I receive iadademstat PO on days 1, 8, 15, and 22 or days 1 and 15 of each cycle. Patients also continue receiving their initial ICI treatment, either atezolizumab IV over 30-60 minutes on day 1 of each cycle or durvalumab IV over 60 minutes on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MUGA or ECHO, brain MRI or brain CT during screening, and CT scans and blood and urine sample collection throughout the trial. Patients may also undergo an optional tumor biopsy on study.

Group II: Phase I (iadademstat, atezolizumab, durvalumab) Experimental Treatment 9 Interventions

Patients in Phase I receive iadademstat PO on days 1, 8, 15, and 22 or days 1 and 15 of each cycle. Patients also continue receiving their initial ICI treatment, either atezolizumab IV over 30-60 minutes on day 1 of each cycle or durvalumab IV over 60 minutes on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MUGA or ECHO, brain MRI or brain CT during screening, and CT scans and blood and urine sample collection throughout the trial. Patients may also undergo an optional tumor biopsy on study.

Group III: Phase II Arm II (atezolizumab, durvalumab) Active Control 8 Interventions

Patients in Phase II Arm II continue receiving their initial ICI treatment, either atezolizumab IV over 30-60 minutes on day 1 of each cycle or durvalumab IV over 60 minutes on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MUGA or ECHO, brain MRI or brain CT during screening, and CT scans and blood and urine sample collection throughout the trial. Patients may also undergo an optional tumor biopsy on study.

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

Approved in United States as Iadademstat for:

• Orphan drug designation for Acute Myeloid Leukemia (AML)

Approved in European Union as Iadademstat for:

• Orphan drug designation for Acute Myeloid Leukemia (AML)

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 349 patients diagnosed with extensive-stage small cell lung cancer (SCLC) in British Columbia, only 36% of those receiving platinum-doublet chemotherapy were eligible for first-line immune checkpoint inhibitors (ICI), highlighting a significant gap in treatment options for the majority of patients.

After one or two cycles of chemotherapy, an additional 11% of patients improved their performance status to become eligible for ICI, suggesting that treatment strategies may need to adapt to include patients with poorer initial health status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world eligibility for platinum doublet plus immune checkpoint inhibitors in extensive-stage small-cell lung cancer. Rittberg, R., Leung, B., Al-Hashami, Z., et al.[2022]

In a phase 1 study involving 17 patients with relapsed or refractory small-cell lung cancer (SCLC), atezolizumab was generally well tolerated, with 64.7% experiencing any-grade treatment-related adverse events, the most common being fatigue.

Atezolizumab showed some antitumor activity, with a partial response in 5.9% of patients and a median overall survival of 5.9 months, suggesting potential benefits for patients with high T-effector gene signature and PD-L1 expression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Activity and Safety of Atezolizumab in a Phase 1 Study of Patients With Relapsed/Refractory Small-Cell Lung Cancer. Chiang, AC., Sequist, LVD., Gilbert, J., et al.[2021]

In a study of 99 previously untreated patients with extensive disease small cell lung cancer (ED-SCLC), adding atezolizumab to the standard carboplatin and etoposide regimen significantly improved overall survival, extending it to 20.8 months compared to 12.1 months for those receiving carboplatin and etoposide alone.

While there was no significant difference in progression-free survival between the two treatment groups, certain subgroups (such as older patients, males, and those with better health status) showed particularly enhanced survival benefits from the addition of atezolizumab, indicating its potential for personalized treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab addition to platinum doublet: evaluating survival outcomes for patients with extensive disease small cell lung cancer. Kubo, S., Kobayashi, N., Matsumoto, H., et al.[2023]

The combination of atezolizumab, a PD-L1 inhibitor, with platinum-based chemotherapy significantly improves overall survival in patients with extensive-stage small cell lung cancer compared to chemotherapy alone.

This research suggests that this combination therapy could become a new first-line treatment option for patients suffering from this aggressive form of lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Study: Atezolizumab Improves Survival in SCLC. [2019]

In a study of 143 small cell lung cancer patients treated with either durvalumab or atezolizumab plus chemotherapy, durvalumab showed a significantly better median overall survival of 22.0 months compared to 10.0 months for atezolizumab (P=0.03).

The addition of radiotherapy to PD-L1 inhibitor therapy may improve long-term survival, but it also increases the risk of immune-related pneumonitis, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of durvalumab + chemotherapy vs. atezolizumab + chemotherapy in the treatment of small‑cell lung cancer: a retrospective comparative cohort study. Zou, Y., Ren, X., Zhang, H., et al.[2023]

Atezolizumab significantly improved overall survival in patients with previously treated non-small-cell lung cancer compared to docetaxel, with median survival times of 13.8 months versus 9.6 months, respectively.

The safety profile of atezolizumab was favorable, with only 15% of patients experiencing grade 3 or 4 adverse events, compared to 43% in the docetaxel group, indicating it may be a safer treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Rittmeyer, A., Barlesi, F., Waterkamp, D., et al.[2022]

Atezolizumab, an anti-PD-L1 therapy, was well tolerated in a study of 45 patients with advanced melanoma, showing that most side effects were mild (grade 1/2) and no treatment-related deaths occurred.

The treatment resulted in a 30% overall response rate and a median overall survival of 23 months, with certain biomarkers like PD-L1 expression and tumor mutational burden linked to better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Clinical Activity, and Biological Correlates of Response in Patients with Metastatic Melanoma: Results from a Phase I Trial of Atezolizumab. Hamid, O., Molinero, L., Bolen, CR., et al.[2020]

Atezolizumab, combined with carboplatin and etoposide, significantly improves overall survival and progression-free survival in patients with extensive-stage small cell lung cancer, based on data from the IMpower133 trial involving previously untreated patients.

The treatment regimen is generally well tolerated, with no new safety concerns identified, and it does not negatively impact patients' quality of life, making it a valuable first-line therapy option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab: A Review in Extensive-Stage SCLC. Frampton, JE.[2021]

Atezolizumab and durvalumab have been approved by the FDA for first-line treatment of extensive stage small cell lung cancer (SCLC) in combination with chemotherapy, showing significant improvements in overall survival (OS) compared to chemotherapy alone, with median OS of 12.3 months and 13.0 months respectively.

Both drugs demonstrated a safety profile consistent with known toxicities of immune-checkpoint inhibitors, marking a significant advancement in treatment options for SCLC, which has seen limited improvements in survival over the past 30 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Atezolizumab and Durvalumab in Combination with Platinum-Based Chemotherapy in Extensive Stage Small Cell Lung Cancer. Mathieu, L., Shah, S., Pai-Scherf, L., et al.[2021]

Durvalumab, while effective for extensive-stage small-cell lung cancer, is not cost-effective compared to atezolizumab, with an incremental cost-effectiveness ratio (ICER) of $165,182 per quality-adjusted life-year (QALY), exceeding the typical willingness-to-pay threshold of $150,000.

The analysis, based on data from two phase 3 clinical trials, suggests that reducing the cost of durvalumab or increasing the willingness-to-pay threshold could improve its cost-effectiveness relative to atezolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-Effectiveness Analysis of Atezolizumab Versus Durvalumab as First-Line Treatment of Extensive-Stage Small-Cell Lung Cancer in the USA. Ionova, Y., Vuong, W., Sandoval, O., et al.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Real-world eligibility for platinum doublet plus immune checkpoint inhibitors in extensive-stage small-cell lung cancer. [2022]

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

Clinical Activity and Safety of Atezolizumab in a Phase 1 Study of Patients With Relapsed/Refractory Small-Cell Lung Cancer. [2021]

3. Germany pubmed.ncbi.nlm.nih.gov

Atezolizumab addition to platinum doublet: evaluating survival outcomes for patients with extensive disease small cell lung cancer. [2023]

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

Study: Atezolizumab Improves Survival in SCLC. [2019]

5. China pubmed.ncbi.nlm.nih.gov

Efficacy and safety of durvalumab + chemotherapy vs. atezolizumab + chemotherapy in the treatment of small‑cell lung cancer: a retrospective comparative cohort study. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. [2022]

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

Safety, Clinical Activity, and Biological Correlates of Response in Patients with Metastatic Melanoma: Results from a Phase I Trial of Atezolizumab. [2020]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Atezolizumab: A Review in Extensive-Stage SCLC. [2021]

9. England pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Atezolizumab and Durvalumab in Combination with Platinum-Based Chemotherapy in Extensive Stage Small Cell Lung Cancer. [2021]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Cost-Effectiveness Analysis of Atezolizumab Versus Durvalumab as First-Line Treatment of Extensive-Stage Small-Cell Lung Cancer in the USA. [2022]