Niraparib + Temozolomide for Small Cell Lung Cancer

(Relapsed SCLC Trial)

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

166 Participants Needed

Trial Summary

What is the purpose of this trial?

Randomized phase 2, multicenter, biomarker directed clinical trial with a safety lead-in to assess the efficacy of Stenoparib plus Temozolomide (TMZ) in relapsed Small Cell Lung Cancer patients. Participants will receive either a combination of oral Stenoparib at the highest tolerated dose with oral Temozolomide 40mg daily or standard of care Lurbinectedin for 21-day cycles. The Dose limiting toxicity period will be 1 cycle of 21 days. This study will explore if the biomarkers the investigators test predict sensitivity to the combination of Stenoparib plus TMZ and therefore leads to a better treatment response. There are two potential tests of biomarkers that can predict who would benefit from the oral combination of Stenoparib with Temozolomide (TMZ), but they have not been evaluated. This study will test for this sensitivity using a biomarker (found in the blood that may be related to how a person reacts to a drug). The study will include 9 participants for the safety evaluation of the Stenoparib+TMZ group and 5 participants for the standard of care Lurbinectedin safety group. We will first determine safety dose for the experiment arm which, will include 3 groups with 3 participants in each group. Three doses of Stenoparib will be evaluated for toxicity. The initial starting dose of Stenoparib will be 200mg po QD. Once the maximum tolerated dose has been determined, participants will be assigned to one of the two groups in the phase 2 portion. Group 1 will be patients that test negative for the biomarker and will receive treatment with Lurbinectedin as per standard of care guidelines. Group 2 will be patients that test positive for the biomarker that will be randomly assigned to either the combination of Stenoparib plus Temozolomide (TMZ) or Lurbinectedin.

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.

What data supports the effectiveness of the drug combination Niraparib and Temozolomide for treating small cell lung cancer?

Research shows that a similar drug combination, olaparib and temozolomide, had a 41.7% response rate in patients with relapsed small-cell lung cancer, suggesting potential effectiveness for Niraparib and Temozolomide as well. Additionally, Niraparib has been effective in prolonging progression-free survival in ovarian cancer, indicating its potential benefit in other cancers. ^{1 2 3 4 5}

Is the combination of Niraparib and Temozolomide safe for humans?

Temozolomide has been shown to be safe in phase I studies for non-prostate cancer patients, indicating it is generally safe for humans. ^{6 7 8 9 10}

What makes the drug combination of Niraparib and Temozolomide unique for treating small cell lung cancer?

The combination of Niraparib and Temozolomide is unique because it uses a PARP inhibitor (Niraparib) to enhance the effectiveness of chemotherapy (Temozolomide) in treating small cell lung cancer, a condition with limited treatment options. This approach is novel as it targets the cancer's DNA repair mechanisms, potentially improving outcomes for patients who have not responded well to standard therapies. ^{1 3 11 12 13}

Research Team

Shadia Jalal, MD

Principal Investigator

Richard L. Roudebush VA Medical Center, Indianapolis, IN

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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 (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]

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]

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]

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]

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 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]

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]

References

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

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

2. Germany 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. [2019]

3. France pubmed.ncbi.nlm.nih.gov

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

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

Pharmaceutical Approval Update. [2020]

5. France pubmed.ncbi.nlm.nih.gov

Niraparib: A Review in Ovarian Cancer. [2019]

6. United States 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. [2022]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Atezolizumab in Patients with Metastatic Urothelial Carcinoma Who Have Progressed After First-line Chemotherapy: Results of Real-life Experiences. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

[89Zr]-Atezolizumab-PET Imaging Reveals Longitudinal Alterations in PDL1 during Therapy in TNBC Preclinical Models. [2023]

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

A phase II study of temozolomide in hormone-refractory prostate cancer. [2018]

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

Safety and Tolerability of PD-1/PD-L1 Inhibitors Compared with Chemotherapy in Patients with Advanced Cancer: A Meta-Analysis. [2022]

11. 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]

12. United States 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. [2023]

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

The poly (ADP ribose) polymerase inhibitor niraparib: Management of toxicities. [2019]