Anti-CD38 + KRAS Vaccine + Anti-PD-1 for Pancreatic & Lung Cancer
(DARANIVOVAX Trial)
Recruiting in Palo Alto (17 mi)
Overseen bySamir Khleif, MD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Georgetown University
Must not be taking: Anti-CD38 therapies, Live vaccines
Disqualifiers: Pregnancy, Active infection, Autoimmune disease, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
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.
12345What 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.
678910How 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.
1341112Eligibility 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.
+10 more
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.
+31 more
Trial 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
Participant Groups
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.
2Treatment groups
Experimental Treatment
Group I: Refractory Non-Small Cell Lung CancerExperimental Treatment3 Interventions
Group II: Pancreatic Ductal AdenocarcinomaExperimental Treatment3 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Georgetown Lombardi Comprehensive Cancer CenterWashington, United States
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Who Is Running the Clinical Trial?
Georgetown UniversityLead Sponsor
Targovax ASAIndustry Sponsor
Bristol-Myers SquibbIndustry Sponsor
Janssen, LPIndustry Sponsor
References
Evaluation of Cyclophosphamide/GVAX Pancreas Followed by Listeria-Mesothelin (CRS-207) with or without Nivolumab in Patients with Pancreatic Cancer. [2023]Label="PURPOSE">Two studies in previously treated metastatic pancreatic cancer have been completed combining GVAX pancreas vaccine (GM-CSF-secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated Listeria monocytogenes-expressing mesothelin). In the current study, we compared Cy/GVAX followed by CRS-207 with (Arm A) or without nivolumab (Arm B).
Overcoming immunosuppression to enhance a p53MVA vaccine. [2021]A Phase I trial of a p53-targeting modified vaccinia Ankara (p53MVA) vaccine in patients afflicted with refractory gastrointestinal cancers demonstrated enhanced T-cell recognition of p53 following vaccination. However, this effect was transient suggesting that p53MVA requires combination with immunomodulatory agents to deliver clinical benefit. Here, we outline our rationale for combining p53MVA with immunomodulatory chemotherapy in a forthcoming trial.
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]The prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) is dismal and conventional chemotherapy treatment delivers limited survival improvement. Immunotherapy may complement our current treatment strategies. We previously demonstrated that the combination of an allogeneic tumour-lysate dendritic cell (DC) vaccine with an anti-CD40 agonistic antibody resulted in robust antitumour responses with survival benefit in a murine PDAC model. In the Rotterdam PancrEAtic Cancer Vaccination-2 trial, we aim to translate our findings into patients. This study will determine the safety of DC/anti-CD40 agonistic antibody combination treatment, and treatment-induced tumour-specific immunological responses.
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]A neoadjuvant immunotherapy platform clinical trial allows for rapid evaluation of treatment-related changes in tumors and identifying targets to optimize treatment responses. We enrolled patients with resectable pancreatic adenocarcinoma into such a platform trial (NCT02451982) to receive pancreatic cancer GVAX vaccine with low-dose cyclophosphamide alone (Arm A; n = 16), with anti-PD-1 antibody nivolumab (Arm B; n = 14), and with both nivolumab and anti-CD137 agonist antibody urelumab (Arm C; n = 10), respectively. The primary endpoint for Arms A/B - treatment-related change in IL17A expression in vaccine-induced lymphoid aggregates - was previously published. Here, we report the primary endpoint for Arms B/C: treatment-related change in intratumoral CD8+ CD137+ cells and the secondary outcomes including safety, disease-free and overall survivals for all Arms. Treatment with GVAX+nivolumab+urelumab meets the primary endpoint by significantly increasing intratumoral CD8+ CD137+ cells (p = 0.003) compared to GVAX+Nivolumab. All treatments are well-tolerated. Median disease-free and overall survivals, respectively, are 13.90/14.98/33.51 and 23.59/27.01/35.55 months for Arms A/B/C. GVAX+nivolumab+urelumab demonstrates numerically-improved disease-free survival (HR = 0.55, p = 0.242; HR = 0.51, p = 0.173) and overall survival (HR = 0.59, p = 0.377; HR = 0.53, p = 0.279) compared to GVAX and GVAX+nivolumab, respectively, although not statistically significant due to small sample size. Therefore, neoadjuvant and adjuvant GVAX with PD-1 blockade and CD137 agonist antibody therapy is safe, increases intratumoral activated, cytotoxic T cells, and demonstrates a potentially promising efficacy signal in resectable pancreatic adenocarcinoma that warrants further study.
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]The granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells vaccine (GVAX) has antitumour activity against prostate cancer; preclinical studies have shown potent synergy when combined with ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen 4. We aimed to assess the safety of combined treatment with GVAX and ipilimumab in patients with metastatic castration-resistant prostate cancer (mCRPC).
An update on the safety of nivolumab for the treatment of advanced melanoma. [2021]Introduction: Due to its unique mechanism of action as an immune checkpoint inhibitor, nivolumab has high antitumor activity, but at the same time this mechanism is responsible for immune-related adverse events that may limit patients' safety and therapy continuation.Areas covered: Long-term safety of nivolumab including 5-year follow-up, safety of nivolumab treatment after ipilimumab therapy, safety of nivolumab in challenging subgroups (elderly, patients with brain metastases, patients with autoimmune disorders), safety of nivolumab in with rare melanoma subtypes (including mucosal melanoma), as well as specificity of AEs reported for nivolumab treatment in melanoma patients in comparison to other cancer types and other immunotherapy molecules, and impact of AEs on response rates and PFS on nivolumab treatment are discussed.Expert opinion: Search for biomarkers that would help us to identify patient populations that may suffer from severe nivolumab toxicity could help in selecting patients that should not be treated with this type of therapy. Novel combinations and immunotherapy drugs including use of NKTR-214 (IL-2 pathway), lymphocyte-activation gene 3 (LAG-3), local injections of talimogene laherparepvec (T-VEC), or systemic use of T-cell receptors agonists such as OX40, CD137, ICOS-1, could provide regimens with limited toxicity and higher activity.
Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. [2022]Nivolumab, a human immunoglobulin G4-blocking antibody against the T-cell programmed death-1 checkpoint protein, has activity against metastatic melanoma. Its safety, clinical efficacy, and correlative biomarkers were assessed with or without a peptide vaccine in ipilimumab-refractory and -naive melanoma.
Dermatological adverse events associated with immune checkpoint inhibitor-based combinations of anticancer therapies: a systematic review. [2022]Aim: This paper presents the reported dermatological adverse events (AEs) associated with approved combinations of immunotherapy with drugs of the same class, or in combination with targeted therapy or chemotherapy. Materials & methods: PubMed was used as an electronic database, and a total of 29 articles were reviewed which reported dermatological AEs following combination therapies with nivolumab, ipilimumab, axitinib, pembrolizumab, lenvatinib, avelumab, atezolizumab, carboplatin, etoposide, paclitaxel, bevacizumab, pemetrexed, cisplatin and durvalumab. Results: The dermatological AEs reported were mutually inclusive and the highest incidence of specific AEs was seen in the following combinations: rash in the nivolumab/ipilimumab and lenvatinib/pembrolizumab combinations, pruritus in the atezolizumab/nab-paclitaxel combination, dry skin and palmar-plantar erythrodysesthesia in the axitinib/pembrolizumab combination, and alopecia and severe skin reactions in the pembrolizumab/carboplatin/paclitaxel combination. Conclusion: Knowledge of such side effects is of benefit when choosing an optimal treatment regimen and should be integrated into the monitoring and follow-up phases of treatment.
Safety and efficacy of nivolumab in the treatment of cancers: A meta-analysis of 27 prospective clinical trials. [2022]Immune checkpoint inhibition therapy has benefited people and shown powerful anti-tumor activity during the past several years. Nivolumab, a fully human IgG4 monoclonal antibody against PD-1, is a widely studied immune checkpoint inhibitor for the treatment of cancers. To assess the safety and efficacy of nivolumab, 27 clinical trials on nivolumab were analyzed. Results showed that the summary risks of all grade adverse effects (AEs) and grade ≥3 AEs were 0.65 and 0.12. The rate of nivolumab-related death was 0.25%. The most common any grade AEs were fatigue (25.1%), rush (13.0%), pruritus (12.5%), diarrhea (12.1%), nausea (11.8%) and asthenia (10.4%). The most common grade ≥3 AEs were hypophosphatemia (only 2.3%) and lymphopenia (only 2.1%). The pooled objective response rate (ORR), 6-month progression-free survival (PFS) rate and 1-year overall survival (OS) rate were 0.26, 0.40 and 0.52, respectively. The odds ratio of ORR between PD-L1 positive and negative was 2.34 (95% CI 1.77-3.10, p
Nivolumab-Induced Severe Akathisia in an Advanced Lung Cancer Patient. [2019]BACKGROUND Nivolumab is an anti-PD-1 immune checkpoint inhibitor that was recently developed for cancer immunotherapy. In the clinical trials of nivolumab, its adverse effects were reported to be less likely than those of conventional anti-cancer agents; however, after practical clinical distribution, it has come to be known that nivolumab induces various immune-related adverse events. CASE REPORT A 58-year-old male with a recurrence of lung adenocarcinoma was treated with nivolumab. Only four days after the initial administration of nivolumab, the patient presented with unbearable restlessness and distress that was resistant to all therapeutic agents used, and it gradually became worse. He finally came to need deep sedation despite his cancer status being stable during the course. Clinical tests including magnetic resonance imaging, cerebrospinal fluid cytology, and antibodies of paraneoplastic syndrome exhibited no signs of encephalitis or another possible cause of the neuropathy. The diagnosis of akathisia could be made only by his somatoform presentation. It was uncertain whether or not this complication was correlated with the activation of his immune system. CONCLUSIONS Anti-immune check point inhibitors may induce many unknown adverse events. Severe akathisia induced by nivolumab, as in our case, has not been reported yet. Collecting every adverse event of nivolumab may be important to make a better algorithm to manage its huge variety of complications.
Predicted Markers of Overall Survival in Pancreatic Cancer Patients Receiving Dendritic Cell Vaccinations Targeting WT1. [2019]We have developed a Wilms' tumor 1 (WT1)-targeting dendritic cell (DC)-based cancer vaccine combined with standard chemotherapy for patients with advanced pancreatic ductal adenocarcinoma (PDA).
Immunotherapy and Prevention of Pancreatic Cancer. [2023]Pancreatic cancer is the third-leading cause of cancer mortality in the USA, recently surpassing breast cancer. A key component of pancreatic cancer's lethality is its acquired immune privilege, which is driven by an immunosuppressive microenvironment, poor T cell infiltration, and a low mutational burden. Although immunotherapies such as checkpoint blockade or engineered T cells have yet to demonstrate efficacy, a growing body of evidence suggests that orthogonal combinations of these and other strategies could unlock immunotherapy in pancreatic cancer. In this Review article, we discuss promising immunotherapies currently under investigation in pancreatic cancer and provide a roadmap for the development of prevention vaccines for this and other cancers.