Triple Drug Combo for Advanced Cancer

(COD Trial)

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and side effects of a new combination of three drugs: Copanlisib Hydrochloride, Durvalumab (Imfinzi), and Olaparib (Lynparza), for treating advanced cancers that have spread or cannot be surgically removed. These drugs block enzymes that aid cancer growth, prevent cancer cells from repairing themselves, and enhance the immune system to attack cancer. The trial targets individuals with advanced solid tumors and specific genetic mutations affecting their cancer. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this new combination therapy.

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.

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

A previous study found copanlisib to be generally safe and promising for patients with certain types of non-Hodgkin lymphoma. Most people tolerated it well, though some experienced side effects. Research on durvalumab shows it is safe for many patients with solid cancers, with manageable side effects. Studies on olaparib in various cancers suggest it is generally well-tolerated, with consistent safety data across several trials.

This trial is an early-phase study, focusing on finding the best dose and understanding the side effects of these drugs when used together. Early-phase trials primarily assess safety, so there is limited information on how these three drugs work in combination. However, each drug has shown a manageable safety profile individually. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this triple drug combo for advanced cancer because it brings together three powerful agents: copanlisib hydrochloride, durvalumab, and olaparib. Unlike many current treatments which might focus on a single pathway, this combination targets multiple aspects of cancer cell survival and immune evasion. Copanlisib hydrochloride disrupts cancer cell growth by inhibiting specific enzymes, durvalumab helps the immune system recognize and attack cancer cells, and olaparib interferes with cancer cells' ability to repair their DNA. This multi-faceted approach could potentially improve effectiveness and overcome resistance seen with other treatments.

What evidence suggests that this trial's treatments could be effective for advanced cancer?

Research has shown that using olaparib and durvalumab together offers significant benefits for treating certain cancers. In some studies, this combination more than doubled the duration of patient response compared to chemotherapy. Olaparib prevents cancer cells from repairing themselves, while durvalumab aids the immune system in identifying and attacking cancer cells. In this trial, participants will receive a combination of olaparib, durvalumab, and copanlisib, which inhibits cancer cell growth, to assess whether it enhances treatment effectiveness. Early results suggest that these drugs together might outperform standard treatments like surgery or radiation for some advanced cancers. ^{4 6 7 8 9}

Who Is on the Research Team?

Timothy A Yap

Principal Investigator

University of Texas MD Anderson Cancer Center LAO

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

See Detailed Description

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

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]

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 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 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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03842228

NCT03842228 | Testing the Combination of the Anti-cancer ... This phase Ib trial seeks to identify the side effects and best dose of the combination of copanlisib and olaparib when given together with durvalumab.

2. withpower.com withpower.com/trial/phase-1-neoplasms-7-2019-8c92f

Triple Drug Combo for Advanced Cancer (COD Trial) This phase Ib trial seeks to identify the side effects and best dose of the combination of copanlisib and olaparib when given together with durvalumab.

3. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2024/lynparza-olaparib-and-imfinzi-durvalumab-demonstrated-strong-clinical-benefit-and-more-than-doubled-median-duration-of-response-vs-chemotherapy-in-patients-with-mismatch-repair-proficient-advanced-or-recurrent-endometrial-cancer.html

LYNPARZA® (olaparib) and IMFINZI® (durvalumab) ... LYNPARZA (olaparib) and IMFINZI (durvalumab) demonstrated strong clinical benefit and more than doubled median duration of response vs. chemotherapy.

4. astrazeneca.com astrazeneca.com/media-centre/press-releases/2023/lynparza-imfinzi-met-endpoint-in-ovarian-cancer.html

Lynparza and Imfinzi combination improved progression ... These data from the DUO-O trial provide encouraging evidence for this Lynparza and Imfinzi combination in patients without tumour BRCA mutations ...

5. appliedclinicaltrialsonline.com appliedclinicaltrialsonline.com/view/phase-iii-trial-data-reinforce-potential-of-imfinzi-and-lynparza-and-imfinzi-regimen-for-endometrial-cancer

Phase III Trial Data Reinforce Potential of Imfinzi and ... Analysis of trial results show Imfinzi and Lynparza displayed a strong clinical benefit and more than doubled median duration of response ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9813077/

Safety and antitumor activity of copanlisib in Japanese ... Overall, copanlisib 60 mg had an acceptable safety profile and showed promising antitumor activity in Japanese patients with relapsed/refractory indolent NHL.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2017/209936Orig1s000MultidisciplineR.pdf

209936Orig1s000 - accessdata.fda.gov The safety profile of copanlisib is tolerable and manageable in patients with relapsed follicular lymphoma, marginal zone lymphoma, small.

8. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/55/NCT02626455/Prot_000.pdf

Clinical Study Protocol Official Title: A Phase III, ... Based on available safety data on copanlisib and to align with copanlisib prescribing information, the dose reduction guidance and ...

9. clinicaltrials.eu clinicaltrials.eu/inn/copanlisib-dihydrochloride/

Copanlisib Dihydrochloride – Application in Therapy and ... This article explores the ongoing research into Copanlisib Dihydrochloride's efficacy and safety in combination with other treatments for conditions such as ...