Anti-CD38 + KRAS Vaccine + Anti-PD-1 for Pancreatic & Lung Cancer

(DARANIVOVAX Trial)

Overseen By Benjamin A. Weinberg

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Georgetown University

Must not be taking: Anti-CD38 therapies, Live vaccines

Disqualifiers: Pregnancy, Active infection, Autoimmune disease, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 8

Duration: approximately 2 years

54 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to test the safety and tolerability of anti-CD38 monoclonal antibody (mAb), daratumumab, in combination with KRAS vaccine (Targovax TG-01/Stimulon QS-21) when given with anti-PD-1 (programmed cell death protein 1) mAb (nivolumab) in patients with advanced non-small cell lung cancer (NSCLC) or pancreatic ductal adenocarcinoma (PDAC). The main questions it aims to answer are: * How well does daratumumab and nivolumab, when given with a vaccine, control or stop these types of cancer? * How well does participants bodies handle these study drugs? * Does this combination of study drugs help participants live longer? Participants will receive daratumumab, nivolumab with KRAS vaccine and have regular tests and procedures to follow how the participants are doing on these study drugs.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, there are specific 'washout' periods (time without taking certain medications) for some treatments, such as a 1-week washout for certain targeted therapies and a 4-week washout for anti-PD-1/PD-L1 therapies. It's best to discuss your current medications with the trial team to understand any specific requirements.

What data supports the effectiveness of the treatment Anti-CD38 + KRAS Vaccine + Anti-PD-1 for Pancreatic & Lung Cancer?

Research shows that combining a cancer vaccine with an anti-PD-1 drug like nivolumab can increase the number of immune cells attacking the tumor, which may improve survival in pancreatic cancer. This suggests that similar combinations, like the one in this trial, could potentially be effective. ^{1 2 3 4 5}

What is known about the safety of nivolumab in cancer treatment?

Nivolumab, used in cancer treatment, can cause side effects like fatigue, rash, and nausea, with serious effects being less common. Some patients may experience severe reactions, such as akathisia (a movement disorder causing restlessness), and it's important to monitor for these during treatment. ^{6 7 8 9 10}

How is the treatment with Daratumumab, KRAS vaccine, and Nivolumab unique for pancreatic and lung cancer?

This treatment is unique because it combines a KRAS vaccine, which targets a specific cancer mutation, with Daratumumab and Nivolumab, which are drugs that help the immune system attack cancer cells. This combination aims to enhance the body's immune response against cancer, offering a novel approach compared to traditional chemotherapy. ^{1 3 4 11 12}

Research Team

Samir Khleif, MD

Principal Investigator

Georgetown University

Eligibility Criteria

This trial is for adults over 18 with advanced non-small cell lung cancer or pancreatic ductal adenocarcinoma that's worsened despite treatment. Participants must have specific KRAS mutations, acceptable organ function, and no other recent cancers or severe illnesses. They can't be pregnant/nursing and must agree to use contraception.

Inclusion Criteria

Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study)

I am willing to give tissue samples for research.

My advanced lung cancer is getting worse despite initial treatment, but it's not rapidly progressing.

Exclusion Criteria

You have a mental illness or social situation that would make it hard for you to follow the study rules.

You have had serious allergic reactions to certain types of medications or vaccines in the past.

You have a history of autoimmune disease or are at risk of developing one.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive daratumumab, nivolumab with KRAS vaccine and have regular tests and procedures

approximately 2 years

Every 8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days following discontinuation of intervention

Long-term Follow-up

Participants are monitored for overall survival and duration of response

approximately 3 years

Treatment Details

Interventions

• Daratumumab
• KRAS vaccine
• Nivolumab

Trial Overview The trial tests daratumumab (anti-CD38 antibody) combined with a KRAS vaccine and nivolumab (anti-PD-1 antibody). It aims to see how well this mix controls cancer, its safety profile, and if it extends life expectancy. Patients will undergo regular monitoring through tests and procedures.

Participant Groups

Group I: Refractory Non-Small Cell Lung Cancer Experimental Treatment 3 Interventions

Group II: Pancreatic Ductal Adenocarcinoma Experimental Treatment 3 Interventions

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

Approved in European Union as Darzalex for:

• Relapsed and refractory multiple myeloma
• Newly diagnosed multiple myeloma in combination with bortezomib, melphalan, and prednisone

Approved in United States as Darzalex for:

• Multiple myeloma in patients who have received at least three prior therapies
• Newly diagnosed multiple myeloma in combination with bortezomib, melphalan, and prednisone
• Relapsed or refractory multiple myeloma in combination with lenalidomide and dexamethasone

Who Is Running the Clinical Trial?

Georgetown University

Lead Sponsor

Trials

355

Recruited

142,000+

Targovax ASA

Industry Sponsor

Trials

6

Recruited

200+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Janssen, LP

Industry Sponsor

Trials

169

Recruited

329,000+

Founded

1953

Headquarters

Beerse, Belgium

Known For

Mental Health Therapies

Top Products

Imodium, Remicade, Invega, Procrit

Joaquin Duato

Janssen, LP

Chief Executive Officer since 2022

MBA from ESADE Business School

Biljana Naumovic

Janssen, LP

Chief Medical Officer since 2023

MD from Belgrade University Medical School

Findings from Research

In a study involving 93 patients with metastatic pancreatic cancer, combining GVAX vaccine and cyclophosphamide with nivolumab (Arm A) did not significantly improve overall survival compared to the same treatment without nivolumab (Arm B), with median survival times of 5.9 and 6.1 months, respectively.

Despite not meeting the primary endpoint, Arm A showed some objective tumor responses and beneficial immunologic changes in long-term survivors, such as increased CD8+ T cells, suggesting potential for immune modulation even if overall survival was similar to standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of Cyclophosphamide/GVAX Pancreas Followed by Listeria-Mesothelin (CRS-207) with or without Nivolumab in Patients with Pancreatic Cancer. Tsujikawa, T., Crocenzi, T., Durham, JN., et al.[2023]

The Phase I trial of the p53-targeting modified vaccinia Ankara (p53MVA) vaccine showed that it can enhance T-cell recognition of the p53 protein in patients with refractory gastrointestinal cancers.

However, the T-cell response was temporary, indicating that combining p53MVA with immunomodulatory agents may be necessary to achieve lasting clinical benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overcoming immunosuppression to enhance a p53MVA vaccine. Hardwick, N., Chung, V., Cristea, M., et al.[2021]

The Rotterdam PancrEAtic Cancer Vaccination-2 trial is investigating the safety and tolerability of a combination treatment using dendritic cell vaccines and an anti-CD40 agonistic antibody in patients with advanced pancreatic cancer, with a focus on those who have not responded to standard chemotherapy.

This phase I trial will include 12 to 18 patients and aims to assess treatment-induced immune responses and tumor-specific effects, potentially offering a new immunotherapy approach for a disease with limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tumour-specific immunological responses of combined dendritic cell vaccination and anti-CD40 agonistic antibody treatment for patients with metastatic pancreatic cancer: protocol for a phase I, open-label, single-arm, dose-escalation study (REACtiVe-2 trial). Lau, SP., van 't Land, FR., van der Burg, SH., et al.[2023]

The combination of GVAX vaccine with nivolumab and urelumab significantly increased the number of activated CD8+ CD137+ T cells in tumors, indicating a robust immune response, and was well-tolerated by patients.

While the median disease-free and overall survival rates were numerically improved with the combination therapy compared to other treatment arms, the results were not statistically significant, suggesting that further studies are needed to confirm these promising findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A platform trial of neoadjuvant and adjuvant antitumor vaccination alone or in combination with PD-1 antagonist and CD137 agonist antibodies in patients with resectable pancreatic adenocarcinoma. Heumann, T., Judkins, C., Li, K., et al.[2023]

The combination of GVAX and 3.0 mg/kg ipilimumab is safe and tolerable for patients with metastatic castration-resistant prostate cancer (mCRPC), with manageable immune-related adverse events observed during the study.

Out of 28 patients, 25% experienced a significant decline in prostate-specific antigen levels, indicating potential efficacy of the treatment, particularly at the 3.0 mg/kg dose level.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. van den Eertwegh, AJ., Versluis, J., van den Berg, HP., et al.[2021]

Nivolumab, an immune checkpoint inhibitor, shows strong antitumor activity but is associated with immune-related adverse events that can affect patient safety and treatment continuation, necessitating careful monitoring.

Long-term safety data, including a 5-year follow-up, suggests that nivolumab can be safely administered to various challenging patient subgroups, but identifying biomarkers for severe toxicity could improve patient selection for this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update on the safety of nivolumab for the treatment of advanced melanoma. Czarnecka, AM., Rutkowski, P.[2021]

Nivolumab, administered at 3 mg/kg with or without a peptide vaccine, was well tolerated and demonstrated a 25% response rate in patients with advanced melanoma, regardless of prior ipilimumab treatment.

The study suggests that nivolumab can induce long-lasting responses, with some patients responding for up to 140 weeks, and highlights the potential for combining or sequencing nivolumab with ipilimumab for better treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. Weber, JS., Kudchadkar, RR., Yu, B., et al.[2022]

A review of 29 articles identified specific dermatological adverse events (AEs) associated with various immunotherapy combinations, highlighting that combinations like nivolumab/ipilimumab and lenvatinib/pembrolizumab had the highest incidence of rash.

Understanding these dermatological AEs, such as pruritus and alopecia, is crucial for optimizing treatment plans and improving patient monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dermatological adverse events associated with immune checkpoint inhibitor-based combinations of anticancer therapies: a systematic review. Salloum, A., Habre, M., Chebl, JA., et al.[2022]

Nivolumab, an immune checkpoint inhibitor, shows a low rate of severe adverse effects (grade ≥3 AEs at 12%) and a very low mortality rate (0.25%), indicating it is a relatively safe treatment option for cancer patients.

In terms of efficacy, nivolumab demonstrates better treatment responses and survival rates compared to traditional chemotherapy, with a 1-year overall survival rate of 52% and a significantly higher objective response rate (ORR) of 26%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of nivolumab in the treatment of cancers: A meta-analysis of 27 prospective clinical trials. Tie, Y., Ma, X., Zhu, C., et al.[2022]

Nivolumab, an anti-PD-1 immune checkpoint inhibitor used for cancer treatment, can induce severe immune-related adverse events, including a rare case of akathisia, which was not previously reported.

This case highlights the need for careful monitoring and documentation of all adverse events associated with nivolumab to improve management strategies for its diverse complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab-Induced Severe Akathisia in an Advanced Lung Cancer Patient. Abe, J., Sato, T., Tanaka, R., et al.[2019]

In a study of 7 patients with advanced pancreatic ductal adenocarcinoma (PDA) receiving a WT1-targeting dendritic cell vaccine combined with chemotherapy, those who responded well (super-responders) had significantly lower levels of plasma matrix metalloproteinase-9 and systemic inflammatory markers compared to non-responders.

Lower cytoplasmic expression of WT1 in PDA cells was also associated with better overall survival, suggesting that both low inflammatory responses and low WT1 expression may serve as predictive markers for patient outcomes in this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predicted Markers of Overall Survival in Pancreatic Cancer Patients Receiving Dendritic Cell Vaccinations Targeting WT1. Ito, Z., Kan, S., Bito, T., et al.[2019]

Pancreatic cancer is highly lethal due to its immune privilege, characterized by an immunosuppressive environment and poor T cell infiltration, making traditional immunotherapies less effective.

Emerging evidence suggests that combining different immunotherapy strategies, such as checkpoint blockade and engineered T cells, may enhance treatment efficacy for pancreatic cancer, highlighting the need for innovative approaches in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy and Prevention of Pancreatic Cancer. Morrison, AH., Byrne, KT., Vonderheide, RH.[2023]

References

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

Evaluation of Cyclophosphamide/GVAX Pancreas Followed by Listeria-Mesothelin (CRS-207) with or without Nivolumab in Patients with Pancreatic Cancer. [2023]

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

Overcoming immunosuppression to enhance a p53MVA vaccine. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Safety and tumour-specific immunological responses of combined dendritic cell vaccination and anti-CD40 agonistic antibody treatment for patients with metastatic pancreatic cancer: protocol for a phase I, open-label, single-arm, dose-escalation study (REACtiVe-2 trial). [2023]

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

A platform trial of neoadjuvant and adjuvant antitumor vaccination alone or in combination with PD-1 antagonist and CD137 agonist antibodies in patients with resectable pancreatic adenocarcinoma. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. [2021]

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

An update on the safety of nivolumab for the treatment of advanced melanoma. [2021]

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

Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Dermatological adverse events associated with immune checkpoint inhibitor-based combinations of anticancer therapies: a systematic review. [2022]

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

Safety and efficacy of nivolumab in the treatment of cancers: A meta-analysis of 27 prospective clinical trials. [2022]

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

Nivolumab-Induced Severe Akathisia in an Advanced Lung Cancer Patient. [2019]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Predicted Markers of Overall Survival in Pancreatic Cancer Patients Receiving Dendritic Cell Vaccinations Targeting WT1. [2019]

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

Immunotherapy and Prevention of Pancreatic Cancer. [2023]