Danvatirsen + Durvalumab for Advanced Resistant Cancers

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Immunosuppressants, Chemotherapy

Disqualifiers: Autoimmune disease, Active infection, 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: 7

Duration: 4 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of combining danvatirsen and durvalumab to treat advanced cancers that no longer respond to standard treatments. Danvatirsen blocks proteins that promote cancer cell growth, while durvalumab, an immunotherapy, aids the immune system in attacking cancer. The trial targets patients with pancreatic cancer, non-small cell lung cancer, or certain types of colorectal cancer that have spread and are unresponsive to other treatments. Suitable candidates have one of these cancers that no longer responds to standard therapy and have not experienced cancer progression after recent treatments. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of participants.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on any concurrent cancer-related treatments like chemotherapy or immunotherapy. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that danvatirsen and durvalumab are likely to be safe for humans?

Research has shown that the combination of danvatirsen and durvalumab is generally safe for patients. In a previous study, patients with advanced solid tumors who took danvatirsen alone or with durvalumab did not experience any new or unexpected side effects. Another study confirmed that using danvatirsen with durvalumab did not lead to any severe or unusual side effects. These findings suggest that this treatment may be safe for those considering joining clinical trials. However, discussing potential risks with a healthcare provider remains important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Danvatirsen and Durvalumab for advanced resistant cancers because it offers a fresh approach to tackling these tough-to-treat diseases. Unlike traditional treatments that often rely on chemotherapy, this combination leverages immune system modulation. Danvatirsen works by targeting the STAT3 protein, which plays a role in cancer cell survival and immune evasion. Meanwhile, Durvalumab is an immune checkpoint inhibitor that enhances the body's immune response against cancer cells. Together, they promise a more targeted attack on cancer cells, potentially leading to improved outcomes for patients who have not responded to existing therapies.

What evidence suggests that danvatirsen and durvalumab might be effective for advanced resistant cancers?

Research has shown that the combination of danvatirsen and durvalumab, which participants in this trial will receive, may help treat certain advanced cancers. Durvalumab, an immunotherapy treatment, has helped some cancer patients live longer by enabling the immune system to attack tumors. Danvatirsen might inhibit proteins that cancer cells need to grow. Early studies suggest this combination could be effective for pancreatic, non-small cell lung, and some colorectal cancers. While more research is needed, initial findings support its potential benefits. ^{1 2 4 5 6}

Who Is on the Research Team?

David Hong, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with advanced pancreatic, non-small cell lung cancer or mismatch repair deficient colorectal cancer that's resistant to treatment. Participants must have a good performance status, measurable disease, and meet specific blood criteria. They should not be pregnant and must agree to use contraception.

Inclusion Criteria

You need to have certain levels of specific components in your blood.

My cancer is confirmed and does not respond to standard treatments.

The patient/legal representative must be willing to provide written consent for collection of formalin fixed paraffin-embedded blocks or slides from archival diagnostic histology samples, where available

Exclusion Criteria

I have not had a live vaccine in the last 28 days.

I have finished my previous cancer treatments and waited the required time before starting a new treatment.

My brain metastases are stable and previously treated.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive danvatirsen intravenously on days 7, 5, and 3 prior to cycle 1, then on days 1, 8, 15, and 22, and durvalumab on day 1. Cycles repeat every 28 days.

4 months

4 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-ups at 30 days, 1-3 months, then every 2 months thereafter.

Up to 4 years

Regular visits every 2 months

What Are the Treatments Tested in This Trial?

Interventions

• Danvatirsen
• Durvalumab

Trial Overview The trial tests danvatirsen (which blocks proteins needed for tumor growth) combined with durvalumab (an immunotherapy antibody). It aims to see if this combo is more effective in treating these cancers compared to current standards.

How Is the Trial Designed?

Group I: Treatment (danvatirsen, durvalumab) Experimental Treatment 2 Interventions

Patients receive danvatirsen IV over 1 hour on days 7, 5 and 3 prior to cycle 1, then on days 1, 8, 15 and 22. Patients also receive durvalumab IV over 1 hour on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Published Research Related to This Trial

The combination of durvalumab and tremelimumab in cancer treatment is associated with a higher incidence of severe adverse events (32.6%) compared to durvalumab alone (23.8%), indicating increased safety concerns with the combination therapy.

Patients receiving the combination therapy also experienced higher rates of specific side effects such as diarrhea (15.6% vs. 8.1%), rash (11.1% vs. 6.5%), and treatment discontinuation (18% vs. 3%), highlighting the need for careful monitoring and patient counseling regarding these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. Fahmy, O., Ahmed, OAA., Khairul-Asri, MG., et al.[2023]

The maximum-tolerated dose (MTD) of vinorelbine (VRL) administered via continuous infusion (CIV) was established at 8 mg/m2 bolus plus 10 mg/m2/day for 4 days, with manageable toxicity primarily involving neutropenia and some mucositis, but minimal neurotoxicity.

The trial demonstrated that VRL is effective in treating advanced breast carcinoma, with a 36% objective response rate and a median survival duration of 24 months, suggesting that CIV administration may provide a better therapeutic index compared to traditional weekly dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II trial of continuous infusion vinorelbine for advanced breast cancer. Toussaint, C., Izzo, J., Spielmann, M., et al.[2018]

In a study of 83 patients with unresectable stage III non-small cell lung cancer (NSCLC) receiving durvalumab, 25.3% experienced pneumonitis, confirming the risk associated with this treatment.

The incidence of pneumonitis observed in this real-world setting aligns with findings from the PACIFIC trial, indicating that the safety profile of durvalumab is consistent in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Incidence of Pneumonitis in Patients Receiving Durvalumab. LeClair, JN., Merl, MY., Cohenuram, M., et al.[2022]

In the phase III PACIFIC trial, durvalumab treatment led to a low incidence of immune-mediated adverse events (imAEs), with any-grade immune-mediated pneumonitis occurring in 9.4% of patients and grade 3/4 imAEs in only 3.4%.

Despite the occurrence of imAEs being more common with durvalumab compared to placebo, these events were generally manageable with treatments like corticosteroids, indicating that the benefits of the PACIFIC regimen outweigh the risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterizing immune-mediated adverse events with durvalumab in patients with unresectable stage III NSCLC: A post-hoc analysis of the PACIFIC trial. Naidoo, J., Vansteenkiste, JF., Faivre-Finn, C., 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 DEDUCTIVE trial is a phase Ib study evaluating the safety and tolerability of combining durvalumab, a PD-L1 inhibitor, with tivozanib, a VEGFR tyrosine kinase inhibitor, in patients with advanced hepatocellular carcinoma (HCC).

Both durvalumab and tivozanib have shown effectiveness as single agents in HCC, but this trial aims to explore their concurrent use, particularly in treatment-naive patients and those who have progressed on other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter, phase Ib/II, open-label study of tivozanib with durvalumab in advanced hepatocellular carcinoma (DEDUCTIVE). Mahmood, S., Li, D., Lee, A., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8190020/

Curative-Intent Treatment with Durvalumab in Early-Stage ... The PD-L1 inhibitor durvalumab demonstrated significant improvements in progression-free survival and overall survival in patients with unresectable, stage III ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02983578

NCT02983578 | Danvatirsen and Durvalumab in Treating ... Giving danvatirsen and durvalumab may work better at treating pancreatic cancer, non-small cell lung cancer and mismatch repair deficient colorectal cancer.

3. nature.com nature.com/articles/s41591-024-02808-y

Biomarker-directed targeted therapy plus durvalumab in ... In this Article, we report the first clinical efficacy, safety, and translational data from four modules of HUDSON in patients who have received ...

4. onclive.com onclive.com/view/ceralasertib-durvalumab-combo-shows-efficacy-in-nsclc-following-anti-pd-l1-therapy

Ceralasertib/Durvalumab Combo Shows Efficacy in ... The combination of ceralasertib plus durvalumab improved overall response rate in patients with non‒small cell lung cancer who progressed on an anti-PD-1/PD-L1 ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9594513/

a phase 1 study - PubMed Central This study is the first to report safety and preliminary efficacy data of combination danvatirsen/durvalumab therapy in Japanese patients. Based on previous ...

6. ir.ionis.com ir.ionis.com/news-releases/news-release-details/phase-1b2-data-durvalumab-plus-danvatirsen-presented-european

Phase 1b/2 Data of Durvalumab Plus Danvatirsen ... The study showed clinical and safety results from a phase 1b/2 trial evaluating danvatirsen, a Generation 2.5 antisense therapy targeting signal transducer ...