Niraparib + Temozolomide for Small Cell Lung Cancer

(Relapsed SCLC Trial)

Not yet recruiting at 11 trial locations

Overseen By Shadia Jalal, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: VA Office of Research and Development

Must not be taking: Lurbinectedin, TMZ, Stenoparib

Disqualifiers: Unstable condition, Acute infection, Cardiovascular disease, MDS, AML, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 2

Duration: 21-day cycles until disease progression or intolerable toxicity

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for individuals with small cell lung cancer that has returned after initial treatment. Researchers aim to determine if a combination of two drugs, Niraparib (also known as Zejula) and Temozolomide, is more effective than the standard treatment, Lurbinectedin. The trial will also assess certain biomarkers (signs in the blood) to identify who will respond best to the new treatment. Individuals who have had small cell lung cancer and received chemotherapy like Carboplatin and Etoposide might be suitable candidates for this study. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on certain antibacterial, antifungal, or antiviral therapies for acute infections, you may need to discuss this with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

In a previous study, the combination of niraparib and temozolomide showed promising results for patients with advanced solid tumors and small cell lung cancer. Most patients tolerated the treatment well, experiencing no severe side effects. Another study found that using niraparib as a maintenance treatment for cancer was safe for most people.

Temozolomide, part of this combination, is already used in cancer treatments, supporting its safety. While every treatment can have side effects, these studies suggest that serious issues are uncommon with this drug mix. Participants can expect regular check-ups during the trial to manage any potential side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Niraparib and Temozolomide for treating small cell lung cancer because of its unique approach. Unlike traditional chemotherapy, which broadly attacks rapidly dividing cells, Niraparib is a PARP inhibitor that targets cancer cells with specific DNA repair vulnerabilities, potentially leading to more precise cancer cell death. When combined with Temozolomide, an oral chemotherapy drug, it may enhance the treatment's effectiveness by exploiting the tumor's weaknesses. This innovative strategy offers hope for improved outcomes in a cancer type notorious for its aggressive nature and limited treatment options.

What evidence suggests that this trial's treatments could be effective for small cell lung cancer?

Research has shown that using niraparib and temozolomide together may help treat small cell lung cancer (SCLC). In this trial, biomarker-positive patients will receive this combination as part of the study drug arm. Earlier studies demonstrated that this combination, along with another drug, extended the time patients lived without their cancer worsening, averaging 4.9 months compared to 1.8 months with another treatment. This suggests it might help control the cancer's growth. The treatment works by preventing cancer cells from repairing their damaged DNA, potentially slowing or stopping tumor growth. Additionally, this combination has proven more effective against advanced solid tumors, like SCLC, in other research settings. ^{2 3 6 7 8}

Who Is on the Research Team?

Shadia Jalal, MD

Principal Investigator

Richard L. Roudebush VA Medical Center, Indianapolis, IN

Are You a Good Fit for This Trial?

This trial is for patients with relapsed Small Cell Lung Cancer. Participants must have specific biomarkers that could predict a better response to the treatment combination of Niraparib and Temozolomide (TMZ). Those without the biomarker will receive Lurbinectedin, a standard care treatment.

Inclusion Criteria

I have received immunotherapy alongside chemotherapy.

I have received Tarlatamab as my second line of treatment.

I will use two forms of birth control from screening until 6 months after the last drug dose.

Exclusion Criteria

I am currently on treatment for a serious infection.

I have previously been treated with lurbinectedin, TMZ, or niraparib.

My blood pressure is high and not well-controlled.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Lead-in

Biomarker positive patients are assigned to one of three doses of Stenoparib to evaluate safety and determine the maximum tolerated dose

3 weeks

1 visit (in-person) per cycle

Treatment

Participants receive either the combination of Stenoparib plus Temozolomide or standard of care Lurbinectedin in 21-day cycles

21-day cycles until disease progression or intolerable toxicity

1 visit (in-person) per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Niraparib
• Temozolomide

Trial Overview The study is testing if certain blood biomarkers can indicate which patients will benefit from taking Niraparib with TMZ versus those who should receive Lurbinectedin. It's a randomized phase 2 trial where participants are divided into two groups based on their biomarker status.

How Is the Trial Designed?

Group I: Study Drug Combination Experimental Treatment 1 Intervention

Biomarker positive patients will be randomized 2:1 to study drug (Stenoparib at the recommended phase 2 dose +TMZ 40mg/day daily) or (Standard of Care) Lurbinectedin 3.2mg/m2 one-hour intravenous (IV) infusion each cycle x21 days until disease progression or intolerable toxicity

Group II: Safety lead-in Experimental Treatment 1 Intervention

Biomarker positive patients will be assigned to one of three doses of Stenoparib (200mg po qd, 200mg po BID, and 200mg in am and 400mg in pm). The initial starting dose will be the 200 mg po QD orally daily for 21 days.

Group III: Standard of Care Active Control 1 Intervention

Lurbinectedin 3.2mg/m2 one-hour intravenous (IV) infusion each cycle x21 days until disease progression or intolerable toxicity

Group IV: Biomarker Negative Standard of Care Active Control 1 Intervention

Lurbinectedin 3.2mg/m2 one-hour intravenous (IV) infusion each cycle x21 days until disease progression or intolerable toxicity

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

Approved in European Union as Zejula for:

• Maintenance treatment of adults with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy
• Maintenance treatment of adults with platinum-sensitive relapsed high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy

Approved in United States as Zejula for:

• Maintenance treatment of adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy
• Treatment of adults with advanced ovarian, fallopian tube, or primary peritoneal cancer treated with three or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD)-positive status

Approved in Canada as Zejula for:

• Maintenance treatment of adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Published Research Related to This Trial

Niraparib is an FDA and EMA-approved oral PARP inhibitor for maintenance treatment in women with recurrent ovarian cancer who have responded to platinum-based chemotherapy, showing efficacy in both BRCA mutated and wild-type cancers.

While niraparib is effective, it can cause significant hematologic toxicities, such as thrombocytopenia and anemia, necessitating dose adjustments for certain patients to minimize these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The poly (ADP ribose) polymerase inhibitor niraparib: Management of toxicities. Moore, KN., Mirza, MR., Matulonis, UA.[2019]

Niraparib (Zejula) is effective for treating recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, providing a targeted therapy option for these specific cancer types.

Ocrelizumab (Ocrevus) has shown efficacy in managing both relapsing and primary progressive multiple sclerosis, while dupilumab (Dupixent) is effective for patients with moderate-to-severe atopic dermatitis, highlighting its role in managing chronic inflammatory skin conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmaceutical Approval Update. Choy, M.[2020]

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 study of 115 patients with metastatic urothelial carcinoma treated with atezolizumab (ATZ) after failing first-line chemotherapy, the objective response rate was 28.7%, indicating that ATZ is effective in this patient population.

The treatment was well tolerated, with 98% of patients experiencing adverse events, but only 21.2% had severe (grade 3-4) treatment-related adverse events, suggesting a manageable safety profile similar to previous clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab in Patients with Metastatic Urothelial Carcinoma Who Have Progressed After First-line Chemotherapy: Results of Real-life Experiences. Tural, D., Ölmez, ÖF., Sümbül, AT., et al.[2022]

Niraparib significantly extends progression-free survival in patients with newly diagnosed advanced ovarian cancer, showing efficacy in both homologous-recombination deficiency positive (HRd) and negative (HRp) populations, based on a phase III trial.

The treatment has a manageable safety profile, with myelosuppression as the main concern, which can be effectively managed through monitoring and individualized dosing based on weight and platelet count.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib: A Review in First-Line Maintenance Therapy in Advanced Ovarian Cancer. Lee, A.[2022]

Niraparib, a recently approved treatment for recurrent platinum-sensitive ovarian cancer, has demonstrated a high oral bioavailability of 72.7% in humans, indicating effective absorption when taken orally.

The study involved six patients who received a therapeutic dose of 300 mg of niraparib, followed by a small intravenous dose to measure its levels in the bloodstream, confirming its potential as a convenient oral treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a 14C-microtracer and therapeutic dose in cancer patients. van Andel, L., Rosing, H., Zhang, Z., et al.[2019]

Niraparib significantly improves progression-free survival and other key outcomes in patients with recurrent, platinum-sensitive ovarian cancer, based on the phase III NOVA trial involving a randomized, double-blind, placebo-controlled design.

The treatment has a manageable safety profile, with most serious side effects being blood-related issues, which can be effectively managed through dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib: A Review in Ovarian Cancer. Heo, YA., Duggan, ST.[2019]

The FDA approved nivolumab combined with ipilimumab and chemotherapy as a first-line treatment for metastatic or recurrent non-small cell lung cancer (NSCLC), based on a study involving 719 patients that showed improved overall survival (OS) of 14.1 months compared to 10.7 months for chemotherapy alone.

Patients receiving the combination treatment also experienced better progression-free survival and overall response rates, indicating that this combination therapy is more effective than traditional chemotherapy alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Nivolumab with Ipilimumab and Chemotherapy for Metastatic Non-small Cell Lung Cancer, A Collaborative Project Orbis Review. Vellanki, PJ., Mulkey, F., Jaigirdar, AA., et al.[2022]

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]

In a phase II study involving 69 patients with limited-stage small-cell lung cancer, the combination of tirapazamine with chemoradiotherapy resulted in a median overall survival of 21 months, which aligns with previous promising results from an earlier pilot study.

Despite some significant toxicities, including grade 3 to 4 esophagitis in 25% of patients, the study demonstrated acceptable safety levels, suggesting that further research into hypoxia-targeted therapies like tirapazamine is justified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of tirapazamine, cisplatin, and etoposide and concurrent thoracic radiotherapy for limited-stage small-cell lung cancer: SWOG 0222. Le, QT., Moon, J., Redman, M., et al.[2023]

The study developed and optimized [89Zr]-Atezolizumab for PET imaging, which allows for noninvasive detection of PD-L1 expression in triple-negative breast cancer (TNBC) tumors, potentially improving treatment monitoring.

Imaging results showed that PD-L1 expression increased after certain therapies, indicating that this method could help assess tumor heterogeneity and response to treatment over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[89Zr]-Atezolizumab-PET Imaging Reveals Longitudinal Alterations in PDL1 during Therapy in TNBC Preclinical Models. Massicano, AVF., Song, PN., Mansur, A., et al.[2023]

Citations

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Niraparib, Temozolomide and Atezolizumab in Treating ... Giving temozolomide, niraparib and atezolizumab may work better in treating patients with advanced solid tumors and extensive-stage small cell lung cancer.

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Niraparib Triplet Shows PFS Benefit vs Atezolizumab as ... Efficacy data revealed that patients treated with the triplet therapy experienced a median PFS of 4.9 months vs 1.8 months with atezolizumab ...

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A phase Ib/II study of niraparib plus temozolomide ... This is a phase 1b/2, randomized, open-label study of TMZ plus niraparib, a PARP inhibitor, with atezolizumab versus atezolizumab as maintenance therapy in ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12248885/

Redefining the Fight Against SCLC: Standards, Innovations ... Tabular overview of recent clinical trials on novel therapeutic approaches in small cell lung cancer (SCLC). This table summarizes key study ...

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<span>A phase I study of niraparib in combination with ... The most common ≥ grade 3 AEs were thrombocytopenia (52.6%), neutropenia (31.6%), and neoplasm progression (15.8%). Based on the in vitro metabolism data, the ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2018.36.15_suppl.8571

Safety and efficacy of combination olaparib (O) and ... Phase Ib/IIa study assessing the safety and efficacy of AL8326 monotherapy in patients with ≥3rd line small cell lung cancer (SCLC) treatment.

7. jto.org jto.org/article/S1556-0864(21)02111-0/fulltext

Efficacy and Safety of Niraparib as Maintenance Treatment ... Nevertheless, niraparib as maintenance therapy modestly improved PFS in patients with platinum-responsive ES-SCLC, with acceptable tolerability ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31416802/

Combination Olaparib and Temozolomide in Relapsed Small ... We performed a phase I/II trial of combination olaparib tablets and temozolomide ... Combination Olaparib and Temozolomide in Relapsed Small-Cell Lung Cancer.