Olaparib + Temozolomide for Neuroendocrine Cancer

Recruiting at 105 trial locations

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Temozolomide, Dacarbazine, PARP inhibitors

Disqualifiers: Pregnancy, Uncontrolled cardiac conditions, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 8

Duration: 39-52 weeks

46 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a combination of two drugs, olaparib and temozolomide, to treat advanced neuroendocrine cancers that have spread or can't be removed by surgery. Olaparib stops cancer cells from repairing themselves, while temozolomide kills them or stops their growth. The goal is to see if this combination works better than using temozolomide alone. Olaparib has shown activity in ovarian and other solid tumors, while temozolomide has been effective in treating various types of neuroendocrine tumors.

Will I have to stop taking my current medications?

The trial requires that you stop taking any strong or moderate CYP3A4 inducers or inhibitors at least 21 days before joining. If you're on enzalutamide or phenobarbital, you need to stop them 5 weeks before. The protocol doesn't specify about other medications, so it's best to discuss with the trial team.

What data supports the effectiveness of the drug combination Olaparib and Temozolomide for neuroendocrine cancer?

Temozolomide has shown effectiveness as a single drug in treating advanced neuroendocrine tumors, and Olaparib is approved for certain types of breast cancer, suggesting potential benefits when combined for neuroendocrine cancer. ^{1 2 3 4 5}

What safety information is available for the combination of Olaparib and Temozolomide?

The combination of Olaparib and Temozolomide has been studied in patients with glioma, where common side effects included fatigue, gastrointestinal issues, and blood-related problems. Some patients needed to reduce their dose or stop treatment due to these side effects. Additionally, Olaparib can worsen the blood-related side effects of Temozolomide. ^{1 2 4 6 7}

How is the drug combination of Olaparib and Temozolomide unique for treating neuroendocrine cancer?

The combination of Olaparib and Temozolomide is unique because it combines Olaparib, a PARP inhibitor (a drug that blocks an enzyme involved in repairing damaged DNA), with Temozolomide, a chemotherapy drug already shown to be effective in treating neuroendocrine tumors. This combination may enhance the effectiveness of treatment by using two different mechanisms to target cancer cells. ^{2 4 8 9 10}

Research Team

Jaydira Del Rivero

Principal Investigator

Alliance for Clinical Trials in Oncology

Eligibility Criteria

Adults with advanced neuroendocrine cancer (pheochromocytoma or paraganglioma) that's spread or can't be surgically removed. Must not have had certain prior treatments, no known allergies to PARP inhibitors, and must agree to contraception. Pregnant/nursing women are excluded.

Inclusion Criteria

My bilirubin levels are normal, except for high levels due to Gilbert's syndrome.

I have never had myelodysplastic syndrome or acute myeloid leukemia.

If you have HIV, your CD4 count must be higher than 250 cells/uL and your HIV viral load must be undetectable within the past 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive temozolomide and olaparib or temozolomide alone, with cycles repeating every 21 or 28 days for up to 13 cycles

39-52 weeks

Regular visits for CT/MRI and blood sample collection

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Every 8 weeks until disease progression, then every 6 months

Treatment Details

Interventions

• Olaparib
• Temozolomide

Trial Overview The trial is testing if adding Olaparib, a drug that prevents tumor cells from repairing DNA damage, to the usual chemotherapy Temozolomide helps more in treating advanced neuroendocrine cancers than chemotherapy alone.

Participant Groups

Group I: Arm I (temozolomide, olaparib) Experimental Treatment 6 Interventions

Patients receive temozolomide PO QD and olaparib PO BID on days 1-7. Treatment with temozolomide repeats every 21 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity. Cycles of olaparib repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT with contrast or MRI throughout the study and undergo mandatory collection of blood samples prior to treatment. Patients may optionally undergo collection of blood samples at the time of progression.

Group II: Arm II (temozolomide) Active Control 5 Interventions

Patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT with contrast or MRI throughout the study and undergo mandatory collection of blood samples prior to treatment. Patients may optionally undergo collection of blood samples at the time of progression.

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

Approved in European Union as Lynparza for:

• Breast cancer
• Ovarian cancer
• Fallopian tube cancer
• Peritoneal cancer
• Pancreatic cancer
• Prostate cancer
• Endometrial cancer

Approved in United States as Lynparza for:

• Ovarian, fallopian tube, and primary peritoneal cancer
• Breast cancer
• Prostate cancer
• Pancreatic cancer

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 20 patients with various types of glioma, the combination of olaparib and temozolomide (TMZ) showed a 50% objective radiographic response rate in patients with recurrent IDH-mutant grade 2-3 gliomas, indicating potential efficacy for this specific group.

While the treatment was generally manageable, common side effects included fatigue and gastrointestinal issues, with 30% of patients requiring dose adjustments due to toxicity, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination Olaparib and Temozolomide for the Treatment of Glioma: A Retrospective Case Series. Schaff, LR., Kushnirsky, M., Lin, AL., et al.[2023]

In a study of 36 patients with advanced neuroendocrine tumors treated with temozolomide, the median time to progression was 7 months, indicating a moderate efficacy of the treatment.

Temozolomide was associated with acceptable toxicity, primarily hematologic, with 14% of patients experiencing severe thrombocytopenia, while 14% showed a radiologic response to the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Ekeblad, S., Sundin, A., Janson, ET., et al.[2022]

In a study of 67 patients with low-grade pituitary tumors, the combination of temozolomide (TMZ) and radiotherapy showed a significantly higher total effective rate (91.89%) compared to radiotherapy alone (70.00%).

The combined treatment resulted in greater reductions in serum levels of prolactin, insulin-like growth factor-1, and growth hormone, indicating enhanced efficacy in managing hormone levels associated with pituitary tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Retrospective Trail Investigating Temozolomide Neoadjuvant Chemotherapy Combined with Radiotherapy in Low-Grade Pituitary Tumors. Cui, J., Shen, J., Ru, X., et al.[2022]

Temozolomide is primarily used for treating refractory central nervous system cancers like anaplastic astrocytoma and glioblastoma, but ongoing clinical trials are exploring its efficacy and safety in newly diagnosed gliomas and other types of tumors.

Research is also investigating different dosing schedules and combinations with other treatments, suggesting that temozolomide could be a versatile option in cancer therapy beyond its current approved uses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future directions for temozolomide therapy. Yung, WK.[2019]

Olaparib (Lynparza) is approved for treating adult patients with high-risk early breast cancer that has a germline BRCA mutation, following chemotherapy treatment.

This approval highlights Olaparib's role as an adjuvant therapy, which means it is used after initial treatments to help prevent cancer recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Adjuvant Treatment for High-Risk Early Breast Cancer. Aschenbrenner, DS.[2022]

Olaparib effectively penetrated recurrent glioblastoma tumors in patients, with measurable concentrations found in all tumor core and margin specimens, indicating its potential for therapeutic use.

The combination of olaparib with low-dose temozolomide (TMZ) was associated with increased hematological toxicity, leading to the need for intermittent dosing, but showed promising efficacy with 36% of patients remaining progression-free at 6 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, safety, and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial. Hanna, C., Kurian, KM., Williams, K., et al.[2022]

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]

In a study of 30 patients with metastatic pancreatic endocrine carcinomas, the combination of capecitabine and temozolomide resulted in a remarkable 70% objective response rate and a median progression-free survival of 18 months.

The treatment showed a high two-year survival rate of 92% with only 12% of patients experiencing severe adverse events, indicating a favorable safety profile compared to traditional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Strosberg, JR., Fine, RL., Choi, J., et al.[2022]

In a study of 65 patients with grade 1/2 neuroendocrine tumors, capecitabine and temozolomide chemotherapy resulted in a response rate of 47.7%, with a median progression-free survival of 16.1 months and overall survival of 38.3 months.

The treatment was generally well-tolerated, with only 13.8% of patients experiencing severe toxicities, indicating that this chemotherapy combination is a promising option for managing both pancreatic and non-pancreatic neuroendocrine tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capecitabine and temozolomide in grade 1/2 neuroendocrine tumors: a Spanish multicenter experience. Crespo, G., Jiménez-Fonseca, P., Custodio, A., et al.[2018]

In a retrospective study of 7 patients with metastatic pancreatic neuroendocrine tumors (pNETs) who had previously failed other treatments, the combination of capecitabine and temozolomide (CAPTEM regimen) resulted in a 43% response rate and 71% clinical benefit, indicating its potential efficacy.

The CAPTEM regimen was well-tolerated, with manageable side effects; the most severe toxicities were grade 3 thrombocytopenia and fatigue, suggesting that this treatment could be a viable option for patients with resistant pNETs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective study of capecitabine/temozolomide (CAPTEM) regimen in the treatment of metastatic pancreatic neuroendocrine tumors (pNETs) after failing previous therapy. Saif, MW., Kaley, K., Brennan, M., et al.[2022]

References

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

Combination Olaparib and Temozolomide for the Treatment of Glioma: A Retrospective Case Series. [2023]

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

Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. [2022]

3. Egypt pubmed.ncbi.nlm.nih.gov

A Retrospective Trail Investigating Temozolomide Neoadjuvant Chemotherapy Combined with Radiotherapy in Low-Grade Pituitary Tumors. [2022]

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

Future directions for temozolomide therapy. [2019]

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

New Adjuvant Treatment for High-Risk Early Breast Cancer. [2022]

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

Pharmacokinetics, safety, and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial. [2022]

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

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

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

First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. [2022]

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

Capecitabine and temozolomide in grade 1/2 neuroendocrine tumors: a Spanish multicenter experience. [2018]

10. Italy pubmed.ncbi.nlm.nih.gov

A retrospective study of capecitabine/temozolomide (CAPTEM) regimen in the treatment of metastatic pancreatic neuroendocrine tumors (pNETs) after failing previous therapy. [2022]