Darzalex Faspro for Blood Cancers
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase < 1
Recruiting
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Must not be taking: Anti-CD38 therapies
Disqualifiers: COPD, Asthma, HIV, Hepatitis, others
No Placebo Group
Breakthrough Therapy
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?This research is being done to investigate the safety and effectiveness of Darzalex Faspro (daratumumab and hyaluronidase-fihj) (a monoclonal antibody that targets plasma cells that make antibodies) and whether it can lower donor specific antibodies (DSA) levels to low enough levels to permit patients to proceed with allogeneic peripheral blood transplant (alloBMT). Those being asked to participate have high DSA levels that puts those being asked to participate at high risk of rejecting the available donor's blood stem cells and making those being asked to participate ineligible to receive a stem cell transplant.
Do I need to stop my current medications for the trial?
The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.
What data supports the effectiveness of the drug Darzalex Faspro for blood cancers?
Research shows that Daratumumab, a key component of Darzalex Faspro, is effective in treating multiple myeloma, a type of blood cancer. It works by targeting a protein on cancer cells, leading to their destruction, and has shown promising results both alone and in combination with other treatments.
12345What makes Darzalex Faspro unique compared to other blood cancer drugs?
Darzalex Faspro is unique because it combines daratumumab, an antibody that targets cancer cells, with hyaluronidase, which helps the drug be absorbed under the skin, allowing for quicker and more convenient subcutaneous (under the skin) administration compared to traditional intravenous (into the vein) treatments.
678910Eligibility Criteria
This trial is for adults with certain blood cancers or conditions like leukemia, lymphoma, and myelodysplastic syndrome who are at high risk of stem cell transplant rejection due to high donor specific antibodies. They must be over 18, willing to participate in a clinical trial, have adequate organ function for the transplant and no other suitable donors.Inclusion Criteria
I am 18 years old or older.
All potential Participants must be pre-approved by BMT faculty consensus.
Subjects are eligible if there are high levels of Donor Specific Antibody levels based on protocol specific scoring system regardless of prior attempts at standard desensitization.
+4 more
Exclusion Criteria
Known hypersensitivity or intolerance to boron or mannitol, sorbitol, corticosteroids, monoclonal antibodies or human proteins, or the excipients.
My lung function is less than half of what is expected for someone my age and size.
I have been treated with Daratumumab or another anti-CD38 therapy before.
+7 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive 4 weekly doses of Darzalex Faspro followed by standard desensitization regimen and allogeneic stem cell transplant
4 weeks
4 visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment, including assessment of DSA levels and recovery metrics
2 years
Participant Groups
The study tests Darzalex Faspro's ability to lower donor specific antibody levels enough for patients to undergo an allogeneic peripheral blood stem cell transplant safely. It aims to see if this treatment can prevent the rejection of transplanted cells in those at high risk.
1Treatment groups
Experimental Treatment
Group I: Daratumumab-SC followed by standard of care DSA desensitization and alloBMTExperimental Treatment2 Interventions
Darzalex Faspro (Daratumumab and hyaluronidase-fihj) will be administered subcutaneously (SC) weekly (every 7 day +/- 1 day) for a total of four doses followed by standard desensitization regimen and allogeneic stem cell transplant.
Darzalex Faspro is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Darzalex Faspro for:
- Newly diagnosed multiple myeloma in combination with lenalidomide and dexamethasone
- Relapsed or refractory multiple myeloma in combination with lenalidomide and dexamethasone
- Newly diagnosed multiple myeloma in combination with bortezomib, melphalan, and prednisone
- Relapsed or refractory multiple myeloma in combination with bortezomib and dexamethasone
- Relapsed or refractory multiple myeloma in combination with pomalidomide and dexamethasone
- Relapsed or refractory multiple myeloma in combination with carfilzomib and dexamethasone
- Monotherapy in patients who have received at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent
🇪🇺 Approved in European Union as Darzalex for:
- Multiple myeloma in combination with lenalidomide and dexamethasone
- Multiple myeloma in combination with bortezomib, melphalan, and prednisone
- Relapsed or refractory multiple myeloma in combination with bortezomib and dexamethasone
- Relapsed or refractory multiple myeloma in combination with pomalidomide and dexamethasone
- Monotherapy in patients who have received at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimore, MD
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Who Is Running the Clinical Trial?
Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsLead Sponsor
Janssen Research & Development, LLCIndustry Sponsor
References
Expanded natural killer cells augment the antimyeloma effect of daratumumab, bortezomib, and dexamethasone in a mouse model. [2023]The use of natural killer (NK) cells is a promising and safe immunotherapeutic approach in the field of cancer immunotherapy. However, combination treatments are required to enhance the effector functions and therapeutic efficacy of NK cells. In this study, we investigated the potential of daratumumab (Dara), bortezomib, and dexamethasone (Dvd) to augment the antitumor effects of NK cells in a multiple myeloma (MM) xenograft mouse model. NK cells were expanded and activated using the K562-OX40 ligand and membrane-bound IL-18 and IL-21 in the presence of IL-2 and IL-15 from peripheral blood mononuclear cells from MM patients. A human MM xenograft model was established using human RPMI8226-RFP-FLuc cells in NOD/SCID IL-2Rγnull (NSG) mice. Tumor-bearing mice were divided into six treatment groups: no treatment, expanded NK cells (eNKs), Dara, Dara + eNKs, Dvd, and Dvd + eNKs. Dvd treatment strongly enhanced the cytotoxicity of eNKs by upregulating expression of NK cell activation ligands, downregulating expression of NK cell inhibitory ligands, and promoting antibody-dependent cellular cytotoxicity. The combination of eNKs with Dvd significantly prolonged mouse survival and reduced the tumor burden and serum M-protein level. Furthermore, Dvd pretreatment significantly increased eNK persistence and homing to MM sites. Our findings suggest that Dvd treatment potentiates the antimyeloma effects of NK cells expanded and activated ex vivo by modulating immune responses in MM-bearing mice.
FcRL5 as a target of antibody-drug conjugates for the treatment of multiple myeloma. [2020]Fc receptor-like 5 (FcRL5/FcRH5/IRTA2/CD307) is a surface protein expressed selectively on B cells and plasma cells. We found that FcRL5 was expressed at elevated levels on the surface of plasma cells from the bone marrow of patients diagnosed with multiple myeloma. This prevalence in multiple myeloma and narrow pattern of normal expression indicate that FcRL5 could be a target for antibody-based therapies for multiple myeloma, particularly antibody-drug conjugates (ADC), potent cytotoxic drugs linked to antibodies via specialized chemical linkers, where limited expression on normal tissues is a key component to their safety. We found that FcRL5 is internalized upon antibody binding, indicating that ADCs to FcRL5 could be effective. Indeed, we found that FcRL5 ADCs were efficacious in vitro and in vivo but the unconjugated antibody was not. The two most effective consisted of our anti-FcRL5 antibody conjugated through cysteines to monomethylauristatin E (MMAE) by a maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (MC-vcPAB) linker (anti-FcRL5-MC-vcPAB-MMAE) or conjugated via lysines to the maytansinoid DM4 through a disulfide linker (anti-FcRL5-SPDB-DM4). These two ADCs were highly effective in vivo in combination with bortezomib or lenalidomide, drugs in use for the treatment of multiple myeloma. These data show that the FcRL5 ADCs described herein show promise as an effective treatment for multiple myeloma.
The Therapeutic CD38 Monoclonal Antibody Daratumumab Induces Programmed Cell Death via Fcγ Receptor-Mediated Cross-Linking. [2022]Emerging evidence suggests that FcγR-mediated cross-linking of tumor-bound mAbs may induce signaling in tumor cells that contributes to their therapeutic activity. In this study, we show that daratumumab (DARA), a therapeutic human CD38 mAb with a broad-spectrum killing activity, is able to induce programmed cell death (PCD) of CD38(+) multiple myeloma tumor cell lines when cross-linked in vitro by secondary Abs or via an FcγR. By comparing DARA efficacy in a syngeneic in vivo tumor model using FcRγ-chain knockout or NOTAM mice carrying a signaling-inactive FcRγ-chain, we found that the inhibitory FcγRIIb as well as activating FcγRs induce DARA cross-linking-mediated PCD. In conclusion, our in vitro and in vivo data show that FcγR-mediated cross-linking of DARA induces PCD of CD38-expressing multiple myeloma tumor cells, which potentially contributes to the depth of response observed in DARA-treated patients and the drug's multifaceted mechanisms of action.
Daratumumab: monoclonal antibody therapy to treat multiple myeloma. [2018]Daratumumab (Darzalex[TM]) is a human monoclonal antibody (MAb) that targets CD38; a surface protein highly expressed across multiple myeloma (MM) cells. Preclinical studies have shown daratumumab induces MM cell death through several mechanisms, including complement-dependent cytotoxicity (CDC) antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), apoptosis upon secondary crosslinking and immunomodulatory effects via a decrease in immune suppressive cells. Daratumumab has a favorable toxicity profile and encouraging clinical activity as a single agent and in combination with lenalidomide in heavily pretreated, relapsed patients in whom other novel agents (such as bortezomib, thalidomide and lenalidomide) and stem cell transplant have already failed. Given the encouraging efficacy and acceptable safety profile, daratumumab has emerged as a novel treatment option for MM both as a monotherapy and in combination with conventional and novel anti-MM agents. This review will focus on preclinical pharmacology, pharmacokinetics, safety and clinical development of daratumumab in MM.
Daratumumab displays in vitro and in vivo anti-tumor activity in models of B-cell non-Hodgkin lymphoma and improves responses to standard chemo-immunotherapy regimens. [2022]CD38 is expressed in several types of non-Hodgkin lymphoma (NHL) and constitutes a promising target for antibody-based therapy. Daratumumab (Darzalex) is a first-in-class anti-CD38 antibody approved for the treatment of relapsed/refractory (R/R) multiple myeloma (MM). It has also demonstrated clinical activity in Waldenström macroglobulinaemia and amyloidosis. Here, we have evaluated the activity and mechanism of action of daratumumab in preclinical in vitro and in vivo models of mantle cell lymphoma (MCL), follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), as monotherapy or in combination with standard chemo-immunotherapy. In vitro, daratumumab engages Fc-mediated cytotoxicity by antibody-dependent cell cytotoxicity and antibody-dependent cell phagocytosis in all lymphoma subtypes. In the presence of human serum, complement-dependent cell cytotoxicity was marginally engaged. We demonstrated by Selective Plane Illumination Microscopy that daratumumab fully penetrated a three-dimensional (3D) lymphoma organoid and decreased organoid volume. In vivo, daratumumab completely prevents tumor outgrowth in models of MCL and FL, and shows comparable activity to rituximab in a disseminated in vivo model of blastic MCL. Moreover, daratumumab improves overall survival (OS) in a mouse model of transformed CD20dim FL, where rituximab showed limited activity. Daratumumab potentiates the antitumor activity of CHOP and R-CHOP in MCL and FL xenografts. Furthermore, in a patient-derived DLBCL xenograft model, daratumumab anti-tumor activity was comparable to R-CHOP and the addition of daratumumab to either CHOP or R-CHOP led to full tumor regression. In summary, daratumumab constitutes a novel therapeutic opportunity in certain scenarios and these results warrant further clinical development.
Cost-effectiveness of denosumab as a bone protective agent for patients with castration resistant prostate cancer. [2018]Fortunately, novel agents are nowadays available for the management of patients with castration-resistant prostate cancer (CRPC). Denosumab is a new bone-protective agent, approved for the prevention and management of skeletal-related events. Studies have demonstrated that denosumab has better efficacy and similar rate of adverse effects in comparison with zoledronic acid, which was the standard bone-protective agent. In the present review we study the cost-effectiveness of denosumab in patients with CRPC.
Results of the ADAPT Phase 3 Study of Rocapuldencel-T in Combination with Sunitinib as First-Line Therapy in Patients with Metastatic Renal Cell Carcinoma. [2021]Rocapuldencel-T is an autologous immunotherapy prepared from mature monocyte-derived dendritic cells (DC), coelectroporated with amplified tumor RNA plus CD40L RNA. This pivotal phase III trial was initiated to investigate the safety and efficacy of a combination therapy dosing regimen of Rocapuldencel-T plus sunitinib in patients with metastatic renal cell carcinoma (mRCC).
Docetaxel, vinorelbine, and zoledronic acid as first-line treatment in patients with hormone refractory prostate cancer: a phase II study. [2018]Combining antineoplastic agents is the key to improving the treatment options for men with hormone refractory prostate cancer (HRPC). The current study investigated the combination of docetaxel, vinorelbine, and zoledronic acid as a first-line treatment for HRPC.
[New therapy concepts for castration-resistant prostate cancer: between hormone manipulation, targeted therapy and chemotherapy]. [2021]Within the last 2 years the therapeutic landscape of castration-resistant prostate cancer (CRPC) has dramatically changed. While chemotherapy with docetaxel has only shown a survival benefit in CRPC patients in the last 10 years, in the meantime 4 approved drugs are available for this indication and approval for immunotherapy with sipuleucel-T is expected. Docetaxel still plays a significant role in the treatment of CRPC but is also a cesura in the therapeutic sequence. For asymptomatic or minimally symptomatic, chemotherapy naive CRPC patients a significant survival benefit was shown for treatment with the androgen biosynthesis inhibitor abiraterone. Clinical data for the antiandrogen enzalutamide are expected shortly for this indication. For patients where docetaxel has failed abiraterone, enzalutamide and cabazitaxel have shown survival benefits in phase III trials. The radionuclide alpharadin not only palliated morbidity induced by bone metastases but also prolonged survival of CRPC patients. This review deals with the various drugs with respect to mode of action, clinical results and indications and will focus on new treatment options, such as targeted therapy with cabozantinib or immunotherapy with sipuleucel-T and prostvac.
The establishment of dendritic cell-tumor fusion vaccines for hormone refractory prostate cancer cell. [2021]Dendritic cell (DC)-based tumor vaccine is an attractive modality for the treatment of hormone-refractory prostate cancer (HRPC) because it has some efficacy and few side effects in patients with poor general conditions. The aim of this study was to establish which is the most effective DC vaccine for the treatment of HRPC. We compared DC vaccine sensitized with tumor lysate and a fusion vaccine of DCs and tumor cells.