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

39 Participants Needed

Trial Summary

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 the combination of Danvatirsen and Durvalumab safe for humans?

Durvalumab, also known as Imfinzi or MEDI4736, has been studied for safety in various cancers. It can cause immune-related side effects, including pneumonitis (lung inflammation), with serious cases being rare. Combining it with other drugs like tivozanib or tremelimumab has shown increased rates of side effects, but these combinations have been generally safe in clinical trials. ^{1 2 3 4 5}

What makes the drug combination of Danvatirsen and Durvalumab unique for treating advanced resistant cancers?

Danvatirsen and Durvalumab work together by targeting the immune system to fight cancer, with Danvatirsen potentially enhancing the effect of Durvalumab, an immune checkpoint inhibitor that helps the immune system recognize and attack cancer cells. This combination is unique because it uses the body's own defenses to target cancer, which is different from traditional chemotherapy that directly kills cancer cells. ^{6 7 8 9 10}

What is the purpose of this trial?

This phase II trial studies how well danvatirsen and durvalumab work in treating patients with pancreatic cancer, non-small cell lung cancer and mismatch repair deficient colorectal cancer that has spread to other places in the body and does not respond to treatment. Danvatirsen may be used to block the production of proteins needed for tumor cell growth. 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 danvatirsen and durvalumab may work better at treating pancreatic cancer, non-small cell lung cancer and mismatch repair deficient colorectal cancer.

Research Team

David Hong, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

References

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

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

2. England pubmed.ncbi.nlm.nih.gov

A multicenter, phase Ib/II, open-label study of tivozanib with durvalumab in advanced hepatocellular carcinoma (DEDUCTIVE). [2023]

3. Switzerland 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. [2023]

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

Real-World Incidence of Pneumonitis in Patients Receiving Durvalumab. [2022]

5. Ireland 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. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Second-line combination chemotherapy with vinorelbine and capecitabine in patients with advanced breast cancer previously treated with anthracyclines and/or taxanes. [2018]

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

Ifosfamide bolus followed by five days continuous infusion in extensively pretreated patients with advanced breast cancer: a phase II study. [2022]

8. Germany pubmed.ncbi.nlm.nih.gov

Biweekly vinorelbine and gemcitabine as second-line and beyond treatment in ovarian cancer. [2022]

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

Phase I/II trial of continuous infusion vinorelbine for advanced breast cancer. [2018]

10. Germany pubmed.ncbi.nlm.nih.gov

Phase II study of oral vinorelbine in combination with capecitabine as second line chemotherapy in metastatic breast cancer patients previously treated with anthracyclines and taxanes. [2022]