Triple Drug Combo for Advanced Cancer

Recruiting at 20 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: MDS/AML, Uncontrolled diabetes, others

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

Compensation: Varies

Number of Visits: 31

Duration: 24 months

39 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase Ib trial studies side effects and best dose of copanlisib and olaparib when given together with durvalumab, and how well they work in treating patients with solid tumors that has spread from where it first started (primary site) to other places in the body (metastatic) or cannot be removed by surgery (unresectable). Copanlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving combinations of copanlisib and olaparib or copanlisib, olaparib, and durvalumab may work better in treating patients with solid tumors compared to usual treatments such as surgery, radiation, or other chemotherapy drugs.

Will I have to stop taking my current medications?

The trial requires a washout period for certain medications. If you are taking strong or moderate CYP3A inhibitors or inducers, you will need to stop them 2-5 weeks before starting the trial. Herbal medications and some anti-arrhythmic therapies are also not allowed during the trial.

What data supports the effectiveness of the drug combination including Copanlisib Hydrochloride, Durvalumab, Imfinzi, MEDI 4736, MEDI-4736, MEDI4736, Olaparib, and Lynparza for advanced cancer?

Research shows that durvalumab, a part of this drug combination, is effective in treating various solid tumors by targeting PD-L1, a molecule that helps cancer cells evade the immune system. Additionally, olaparib (Lynparza) is effective in treating certain types of breast and ovarian cancers, suggesting potential benefits when used in combination with other cancer drugs. ^{1 2 3 4 5}

What safety data exists for the triple drug combo including Copanlisib Hydrochloride, Durvalumab, and Olaparib?

Durvalumab is approved for use after chemoradiotherapy in certain lung cancer patients, suggesting it has been deemed safe for use in humans. Olaparib has been studied in combination with other treatments for lung cancer, indicating it has been evaluated for safety in humans. ^{6 7 8 9 10}

What makes the triple drug combo for advanced cancer unique?

The triple drug combo for advanced cancer is unique because it combines Copanlisib Hydrochloride, Durvalumab, and Olaparib, which target different pathways in cancer cells. This combination may offer a novel approach by potentially enhancing the immune response against cancer and inhibiting cancer cell repair mechanisms, unlike standard treatments that typically focus on one pathway. ^{11 12 13 14 15}

Research Team

Timothy A Yap

Principal Investigator

University of Texas MD Anderson Cancer Center LAO

Eligibility Criteria

This trial is for adults with advanced solid tumors that have spread or can't be removed by surgery, and who haven't responded to standard treatments. Participants must have specific gene mutations (like BRCA1/2 or PTEN), meet certain blood and organ function criteria, not be pregnant or breastfeeding, agree to use contraception if of childbearing potential, and cannot have had certain recent treatments or uncontrolled illnesses.

Inclusion Criteria

My heart's pumping ability is normal or above.

My kidney function, measured by GFR, is 51 mL/min or higher.

I can take medication to prevent nausea as usual.

Exclusion Criteria

I have not had major surgery within the last 28 days.

I am allergic to certain cancer drugs or their ingredients.

I have severe heart disease.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive copanlisib hydrochloride IV and olaparib PO, with durvalumab added from cycle 2. Cycles repeat every 28 days for up to 24 months.

24 months

IV on days 1 and 15 or days 1, 8, and 15; PO BID on days 1-28 of each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up visits every 3 months for up to 2 years.

2 years

Follow-up at 30 days post-treatment, then every 3 months

Treatment Details

Interventions

• Copanlisib Hydrochloride
• Durvalumab
• Olaparib

Trial Overview The trial tests a combination of three anti-cancer drugs: Copanlisib (blocks enzymes for cell growth), Olaparib (stops tumor cells from repairing DNA damage), and Durvalumab (helps the immune system attack cancer). It aims to find the best dose with acceptable side effects and see if this combo works better than current treatments.

Participant Groups

Group I: Treatment (copanlisib hydrochloride, olaparib, and durvalumab) Experimental Treatment 9 Interventions

Patients receive copanlisib hydrochloride IV over 1 hour on days 1 and 15 or days 1, 8, and 15 depending on dose level and olaparib PO BID on days 1-28 of each cycle. Beginning cycle 2, patients receive durvalumab IV over 1 hour on day 1 of each cycle. Cycles repeat every 28 days for 24 months in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood samples at baseline within 7 days of C1D1, days 8 and 15 of cycle 1 and day 15 of subsequent cycles, at time of restaging, and end of treatment/progression. Patients undergo x-ray, CT, and MRI at the end of cycle 2 and then every 8 weeks. Patients also undergo an ECHO during pre-study within 28 days of C1D1 and tumor biopsy at baseline within 7 days of C1D1 and day 15 of cycle 1 or 2, and may undergo an optional biopsy at end of treatment/progression.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

The combination of durvalumab and tremelimumab showed improved disease control rates in patients with head and neck squamous cell carcinoma compared to tremelimumab alone, indicating its potential efficacy in this cancer type.

The combination therapy had a tolerable safety profile, with no significant increase in treatment-related adverse events compared to monotherapy, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab and tremelimumab combination therapy versus durvalumab or tremelimumab monotherapy for patients with solid tumors: A systematic review and meta-analysis. Wang, BC., Li, PC., Fan, JQ., et al.[2022]

Durvalumab, a PD-L1 inhibitor, has been shown to be safe for patients with various solid tumors, with common side effects including pruritus and fatigue, based on a meta-analysis of 17 studies involving 1,529 patients.

Higher levels of PD-L1 expression in tumors are linked to better treatment responses to durvalumab, indicating that PD-L1 could serve as a useful biomarker for predicting the drug's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. Yang, H., Shen, K., Zhu, C., et al.[2022]

Niraparib has been approved by the FDA for patients with complete or partial response to first-line platinum-based chemotherapy, regardless of their BRCAm or HRD status, expanding treatment options for more patients.

Olaparib, in combination with bevacizumab, has also received FDA approval for patients with epithelial ovarian cancer, indicating that PARP inhibitors are now beneficial not only for BRCAm and HRD-deficient patients but also for those with HRD-proficient tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PARP inhibitors in the treatment of ovarian cancer: a review. Washington, CR., Moore, KN.[2023]

The combination of MEDI0680 and durvalumab was found to be safe and tolerable in patients with advanced clear-cell renal cell carcinoma, but it did not show improved efficacy compared to nivolumab alone, with objective response rates of 16.7% for the combination and 23.8% for nivolumab.

Both treatment groups had a median progression-free survival of 3.6 months, and a notable percentage of patients (23.8% in the combination group) discontinued treatment due to adverse events, highlighting the need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma. Voss, MH., Azad, AA., Hansen, AR., et al.[2023]

Pembrolizumab combined with adjuvant chemotherapy significantly improves one-year survival rates, overall response rates, and progression-free survival in patients with advanced non-small cell lung cancer (NSCLC), based on a meta-analysis of 14 studies.

This treatment not only enhances efficacy but also reduces the incidence of adverse drug reactions, indicating a favorable safety profile, although further validation through larger randomized controlled trials is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Efficacy and Safety Analysis of PD-1/PD-L1 Inhibitor vs. Chemotherapy in the Treatment of Advanced Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis. Guo, WW., Zhang, TW., Wang, BL., et al.[2023]

The KEYLYNK-012 study is a phase III clinical trial evaluating the effectiveness of pembrolizumab combined with chemoradiotherapy in patients with stage III non-small-cell lung cancer (NSCLC), involving participants aged 18 and older with unresectable disease.

This study aims to determine if the addition of pembrolizumab, with or without olaparib, improves progression-free survival and overall survival compared to standard concurrent chemoradiotherapy, with enrollment ongoing at around 190 sites.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and Design of the Phase III KEYLYNK-012 Study of Pembrolizumab and Concurrent Chemoradiotherapy Followed by Pembrolizumab With or Without Olaparib for Stage III Non-Small-Cell Lung Cancer. Jabbour, SK., Cho, BC., Bria, E., et al.[2022]

Combination therapy with pembrolizumab and lenvatinib is effective as a first-line treatment for clear cell renal carcinoma and as a second-line option for recurrent or metastatic endometrial carcinoma, based on data from five completed clinical trials and two ongoing trials.

This non-chemotherapy regimen helps spare patients from prolonged myelosuppression and lowers the risk of infection, making it a safer alternative for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined use of pembrolizumab and lenvatinib: A review. Eisinger, C., Muluneh, B.[2023]

In a study of 104 patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib, pembrolizumab showed an objective response rate of 18.3% and a median duration of response of 21 months, indicating its effectiveness as a treatment option.

After approximately 2.5 years of follow-up, pembrolizumab demonstrated durable anti-tumor activity with manageable safety, as most treatment-related adverse events were low grade, and no new safety concerns were identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated efficacy and safety of KEYNOTE-224: a phase II study of pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. Kudo, M., Finn, RS., Edeline, J., et al.[2022]

The combination of the PD-L1 inhibitor atezolizumab with standard chemotherapy significantly improves overall survival in patients with metastatic triple-negative breast cancer compared to chemotherapy alone.

This research suggests that adding atezolizumab could provide a new treatment option for patients suffering from this aggressive form of breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-L1 Inhibitor Improves Survival in TNBC. [2019]

In a study involving 125 Chinese patients with metastatic squamous non-small cell lung cancer (NSCLC), pembrolizumab combined with chemotherapy significantly improved overall survival (OS) and progression-free survival (PFS) compared to placebo plus chemotherapy, with hazard ratios of 0.44 and 0.35, respectively.

Patients receiving pembrolizumab-chemotherapy also reported better quality of life and had a longer time before experiencing worsening symptoms like cough and chest pain, indicating that this treatment not only extends survival but also maintains health-related quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Plus Chemotherapy for Chinese Patients With Metastatic Squamous NSCLC in KEYNOTE-407. Cheng, Y., Zhang, L., Hu, J., et al.[2022]

In a study of 78 patients with recurrent or metastatic squamous cell carcinoma of the head and neck, treatment with immune checkpoint inhibitors (CPI), either alone or combined with chemotherapy, showed a median progression-free survival (PFS) of 4 months and a median overall survival (OS) of 11 months, indicating the treatment's effectiveness.

The overall response rate was 20.5% and the disease control rate was 46.1%, with the safety profile of immune-related adverse events being consistent with existing data, supporting the use of CPI therapy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world Data of Palliative First-line Checkpoint Inhibitor Therapy for Head and Neck Cancer. Wagner, SM., Magnes, T., Melchardt, T., et al.[2023]

In the KEYNOTE-355 trial, patients with previously untreated metastatic triple-negative breast cancer (mTNBC) who received pembrolizumab combined with chemotherapy experienced a significant improvement in quality-adjusted survival, gaining an average of 3.7 months more time without symptoms or treatment toxicity compared to those receiving chemotherapy alone.

The benefits of pembrolizumab plus chemotherapy increased over time, with a 20% relative gain in quality-adjusted survival at a maximum follow-up of 52 months, indicating both efficacy and manageable safety in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Q-TWiST analysis of pembrolizumab combined with chemotherapy as first-line treatment of metastatic triple-negative breast cancer that expresses PD-L1. Huang, M., O'Shaughnessy, J., Haiderali, A., et al.[2023]

References

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

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

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

Durvalumab and tremelimumab combination therapy versus durvalumab or tremelimumab monotherapy for patients with solid tumors: A systematic review and meta-analysis. [2022]

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

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. [2022]

4. England pubmed.ncbi.nlm.nih.gov

PARP inhibitors in the treatment of ovarian cancer: a review. [2023]

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

A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma. [2023]

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

Clinical Efficacy and Safety Analysis of PD-1/PD-L1 Inhibitor vs. Chemotherapy in the Treatment of Advanced Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis. [2023]

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

Impact of concomitant medication use and immune-related adverse events on response to immune checkpoint inhibitors. [2021]

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

Rationale and Design of the Phase III KEYLYNK-012 Study of Pembrolizumab and Concurrent Chemoradiotherapy Followed by Pembrolizumab With or Without Olaparib for Stage III Non-Small-Cell Lung Cancer. [2022]

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

Combined use of pembrolizumab and lenvatinib: A review. [2023]

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

Updated efficacy and safety of KEYNOTE-224: a phase II study of pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. [2022]

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

PD-L1 Inhibitor Improves Survival in TNBC. [2019]

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

Pembrolizumab Plus Chemotherapy for Chinese Patients With Metastatic Squamous NSCLC in KEYNOTE-407. [2022]

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

Pembrolizumab plus chemotherapy in Japanese patients with triple-negative breast cancer: Results from KEYNOTE-355. [2023]

14. Greece pubmed.ncbi.nlm.nih.gov

Real-world Data of Palliative First-line Checkpoint Inhibitor Therapy for Head and Neck Cancer. [2023]

15. England pubmed.ncbi.nlm.nih.gov

Q-TWiST analysis of pembrolizumab combined with chemotherapy as first-line treatment of metastatic triple-negative breast cancer that expresses PD-L1. [2023]