Evomela + Fludarabine + TBI for Multiple Myeloma
Recruiting in Palo Alto (17 mi)
Overseen byMehdi Hamadani
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Waitlist Available
Sponsor: Medical College of Wisconsin
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?
This is an open-label, single-arm, phase II study to determine the safety of propylene glycol-free melphalan HCl (EVOMELA®), in combination with fludarabine and total-body irradiation-based reduced-intensity conditioning for haploidentical transplantation. In addition, the study evaluates the one-year progression-free survival of patients undergoing this treatment.
Do I need to stop taking my current medications for this trial?
The trial protocol does not specify whether 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 idea that Evomela + Fludarabine + TBI for Multiple Myeloma is an effective treatment?
The available research shows that the combination of Evomela (Melphalan), Fludarabine, and Total Body Irradiation (TBI) is effective in treating multiple myeloma. In a study comparing different regimens, the combination with TBI (FluMelTBI-75) showed improved survival and disease control compared to a regimen without TBI. Specifically, patients who were not in complete remission had better outcomes with the TBI regimen. Additionally, this combination was better tolerated, with fewer side effects like mouth sores. This suggests that adding TBI to the treatment can enhance its effectiveness while reducing some side effects.12345
What safety data is available for the treatment of Evomela, Fludarabine, and TBI in Multiple Myeloma?
The combination of Fludarabine and Melphalan, with or without Total Body Irradiation (TBI), has been studied in various clinical trials. Regimen-related toxicities include renal, hepatic, mucosal, cardiac, and pulmonary issues, with some cases leading to death. Myelosuppression is a dose-limiting toxicity for Fludarabine, and neurotoxicity has been noted at high doses. The addition of TBI to Fludarabine and Melphalan regimens has been explored to improve outcomes, but it also presents risks of significant non-relapse mortality, especially in older patients or those with prior transplants. Overall, while these regimens can lead to durable remission, they are associated with considerable toxicity.12467
Is the treatment Evomela, Fludarabine, and Total Body Irradiation promising for Multiple Myeloma?
The treatment using Evomela, Fludarabine, and Total Body Irradiation is considered promising for Multiple Myeloma because it combines different approaches to target the cancer cells effectively. Evomela and Fludarabine are drugs that help destroy cancer cells, while Total Body Irradiation uses radiation to kill cancer cells throughout the body. This combination aims to improve treatment outcomes by attacking the cancer in multiple ways.89101112
Eligibility Criteria
This trial is for adults with blood cancers like multiple myeloma who need a haploidentical transplant. They should have good heart and lung function, stable liver and kidney health, no uncontrolled infections or serious illnesses, and agree to use effective contraception.Inclusion Criteria
Transplant recipient able to give informed consent
Your lung function is at least 50% of what is expected for someone of your age and size.
I do not have any ongoing serious infections.
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Exclusion Criteria
My condition is active AML or MDS.
I do not have a suitable family or unrelated donor for a transplant.
I don't have any serious health or mental conditions that could stop me from completing the treatment.
Treatment Details
Interventions
- Evomela (Alkylating agents)
- Fludarabine (Anti-metabolites)
- Total Body Irradiation (Radiation)
Trial OverviewThe study tests EVOMELA® combined with Fludarabine and Total Body Irradiation as a conditioning treatment before haploidentical transplantation. It's an open-label phase II trial focusing on safety and one-year progression-free survival rates.
Participant Groups
1Treatment groups
Experimental Treatment
Group I: MEL/FLU and Total-Body Irradiation (TBI)Experimental Treatment3 Interventions
For patients who are \< 60 years.
* Melphalan: 140 mg/m2/day IV on Day: -6
* Fludarabine: 40 mg/ m2/day IV Days: -5 -4, -3, -2 (Adults: creatinine clearance (CrCl) may be estimated by the Cockcroft Formula: CrCl = \[(140-age) x weight (kg) x 0.85 (for women only)\]/ \[72 x creat (mg/dl)\].)
* TBI: 200 cGy Day: -1.
For patients who are ≥60 years and/or Hematopoietic Cell Transplant-Co-morbidity Index (HCT-CI) score of \>3 (at the discretion of treating physician will have an option to receive):
* Melphalan: 70 mg/m2/day IV on Day -6.
* Fludarabine: 40 mg/m2/day IV Days -5, -4, -3, -2.
* TBI: 200 cGy; Days -1.
Evomela is already approved in United States, European Union, Japan for the following indications:
🇺🇸 Approved in United States as Evomela for:
- Multiple Myeloma
🇪🇺 Approved in European Union as Alkeran for:
- Multiple Myeloma
- Malignant Lymphoma
- Lymphoblastic and Myeloblastic Leukemia
- Childhood Neuroblastoma
- Ovarian Cancer
- Mammary Adenocarcinoma
- Uveal Melanoma
🇯🇵 Approved in Japan as Melphalan for:
- Multiple Myeloma
- Malignant Lymphoma
- Lymphoblastic and Myeloblastic Leukemia
- Childhood Neuroblastoma
- Ovarian Cancer
- Mammary Adenocarcinoma
- Uveal Melanoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Froedtert Hospital & the Medical College of WisconsinMilwaukee, WI
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Who Is Running the Clinical Trial?
Medical College of WisconsinLead Sponsor
References
In vitro and in vivo activity of melflufen (J1)in lymphoma. [2019]Melphalan has been used in the treatment of various hematologic malignancies for almost 60 years. Today it is part of standard therapy for multiple myeloma and also as part of myeloablative regimens in association with autologous allogenic stem cell transplantation. Melflufen (melphalan flufenamide ethyl ester, previously called J1) is an optimized derivative of melphalan providing targeted delivery of active metabolites to cells expressing aminopeptidases. The activity of melflufen has compared favorably with that of melphalan in a series of in vitro and in vivo experiments performed preferentially on different solid tumor models and multiple myeloma. Melflufen is currently being evaluated in a clinical phase I/II trial in relapsed or relapsed and refractory multiple myeloma.
Reduced-Intensity Conditioning with Fludarabine, Melphalan, and Total Body Irradiation for Allogeneic Hematopoietic Cell Transplantation: The Effect of Increasing Melphalan Dose on Underlying Disease and Toxicity. [2022]Disease relapse and toxicity are the shortcomings of reduced-intensity conditioning (RIC) for allogeneic hematopoietic cell transplantation (alloHCT). We hypothesized that adding total body irradiation (TBI) to and decreasing melphalan (Mel) from a base RIC regimen of fludarabine (Flu) and Mel would increase cytoreduction and improve disease control while decreasing toxicity. We performed a phase II trial of Flu 160 mg/m2, Mel 50 mg/m2, and TBI 400 cGy (FluMelTBI-50, n = 61), followed by a second phase II trial of Flu 160 mg/m2, Mel 75 mg/m2, and TBI 400cGy (FluMelTBI-75, n = 94) as RIC for alloHCT. Outcomes were compared with a contemporaneous cohort of 162 patients who received Flu 125 mg/m2 and Mel 140 mg/m2. Eligibility criteria were equivalent for all 3 regimens. All patients were ineligible for myeloablative/intensive conditioning. The median (range) follow-up for all patients was 51 (15 to 103) months. Day 100 donor lymphoid chimerism and transplant-related mortality, neutrophil and platelet engraftment, acute and chronic graft versus host disease incidence, overall survival (OS), and progression-free survival (PFS) were equivalent between FluMel, FluMelTBI-50, and FluMelTBI-75. Stomatitis wasdecreased for FluMelTBI versus FluMel (P < .01). PFS for patients not in complete remission on alloHCT was improved for FluMelTBI-75 versus FluMel (P = .03). On multivariate analysis, OS (P = .05) and PFS (P = .05) were significantly improved for FluMelTBI-75 versus FluMel. FluMelTBI-75 is better tolerated than FluMel, with improved survival and disease control.
Total body irradiation, fludarabine, melphalan, and allogeneic hematopoietic stem cell transplantation for advanced pediatric hematologic malignancies. [2013]We evaluated the efficacy and toxicity of adding 9 Gy of total body irradiation (TBI), in three single daily fractions of 3 Gy, to the reduced intensity regimen of fludarabine 30 mg/m2 i.v. x 4 days and melphalan 140 mg/m2 i.v. x 1 day in advanced pediatric hematologic malignancies. Twenty-two acute lymphoblastic leukemia (ALL), six acute myeloid leukemia (AML), and one non-Hodgkin lymphoma patients were transplanted. Of these, 13 were beyond second remission, and five had prior hematopoietic stem cell transplant (HSCT). Twenty-one donors were unrelated, of which 19 were from cord blood (CB) units. Three of the eight related donors were genotypically disparate. Oral mucositis and diarrhea were the most common toxicities. Twenty-seven patients achieved neutrophil engraftment (median 16 days), and 23 had platelet engraftment (median 42 days). One patient had primary graft failure. Seven patients died of non-relapse causes in the first 100 days. With a median follow-up of 52 months, seven of 22 ALL, five of six AML, and one of one lymphoma patients are alive and in remission. The regimen of TBI, fludarabine, and melphalan allows the engraftment of allogeneic hematopoietic stem cells (including mismatched CB). It was fairly well tolerated in pediatric patients, even for second transplants. Its efficacy requires further evaluation.
Regimen-related toxicity after fludarabine-melphalan conditioning: a prospective study of 31 patients with hematologic malignancies. [2013]A total of 31 consecutive patients with hematologic malignancies who were considered poor candidates for TBI underwent allogeneic stem cell transplantation after conditioning with fludarabine and melphalan. A total of 25 matched sibling recipients received fludarabine 25 mg/m(2) x 5 days and melphalan 70 mg/m(2) x 2 days. For unrelated and haploidentical donor recipients, fludarabine was increased to 30 mg/m(2) and ATG 30 mg/kg x 4 days was added. Graft-versus-host disease prophylaxis consisted of tacrolimus and mini methotrexate. All patients engrafted. Regimen-related toxicity was considerable and included mainly renal, hepatic and mucosal toxicity. There were seven regimen-related-deaths including two VOD, two pulmonary, one renal, one cardiac and one mucosal toxicity. One case of fatal pulmonary toxicity death could be attributed to pre-existing pulmonary damage. Progression-free survival at 12 months was 44% (90% CI: 30-58%) for recipients of HLA-identical sibling transplants and 33% (90% CI: 21-45%) for all patients. In conclusion, the fludarabine-melphalan regimen leads to consistent engraftment. The regimen-related toxicity is considerable and cannot be explained solely by patient selection. Cardiac toxicity is emerging as a unique toxicity of this regimen. Despite toxicity, fludarabine-melphalan has considerable activity and leads to durable remission in a proportion of patients.
Elranatamab in relapsed or refractory multiple myeloma: the MagnetisMM-1 phase 1 trial. [2023]Multiple myeloma (MM) is a plasma cell malignancy expressing B cell maturation antigen (BCMA). Elranatamab, a bispecific antibody, engages BCMA on MM and CD3 on T cells. The MagnetisMM-1 trial evaluated its safety, pharmacokinetics and efficacy. Primary endpoints, including the incidence of dose-limiting toxicities as well as objective response rate (ORR) and duration of response (DOR), were met. Secondary efficacy endpoints included progression-free survival (PFS) and overall survival (OS). Eighty-eight patients with relapsed or refractory MM received elranatamab monotherapy, and 55 patients received elranatamab at efficacious doses. Patients had received a median of five prior regimens; 90.9% were triple-class refractory, 29.1% had high cytogenetic risk and 23.6% received prior BCMA-directed therapy. No dose-limiting toxicities were observed during dose escalation. Adverse events included cytopenias and cytokine release syndrome. Exposure was dose proportional. With a median follow-up of 12.0 months, the ORR was 63.6% and 38.2% of patients achieving complete response or better. For responders, the median DOR was 17.1 months. All 13 patients evaluable for minimal residual disease achieved negativity. Even after prior BCMA-directed therapy, 53.8% achieved response. For all 55 patients, median PFS was 11.8 months, and median OS was 21.2 months. Elranatamab achieved durable responses, manageable safety and promising survival for patients with MM. ClinicalTrials.gov Identifier: NCT03269136 .
Phase I clinical trials with fludarabine phosphate. [2013]There have been six different phase I trials of Fludara I.V. (fludarabine phosphate) in patients with solid tumors and three different phase I trials of Fludara I.V. in patients with acute leukemia. In addition, one trial of the agent given intraperitoneally has also been published. In patients with solid tumors, the two most often used schedules are a daily bolus schedule of 18 to 25 mg/m2/d for 5 days repeated every 28 days, and a 20 mg/m2 loading dose followed by a 48-hour continuous infusion of the agent at a dose of 25 to 30 mg/m2/d. The dose-limiting toxicity in these studies has been myelosuppression. No dosage or schedule could be recommended for patients with acute leukemia because of the severe neurotoxicity (progressive dementia with blindness leading to coma) noted with doses greater than or equal to 96 mg/m2/d for 5 to 7 days. Other toxicities noted in phase I trials have included somnolence, mild to moderate nausea and vomiting, and a rare and reversible interstitial pneumonitis. Of greatest interest is that a profound lymphopenia has been noted as a side effect of Fludara I.V. That toxicity has proven to be of benefit for patients with chronic lymphocytic leukemia, low-grade lymphoma, and mycosis fungoides, all of which are responsive to Fludara I.V. therapy.
Outcomes of Fludarabine, Melphalan and Total Body Irradiation as a Reduced Intensity Conditioning Regimen in Matched Donor Allogeneic Peripheral Blood Stem Cell Transplantation. [2021]Fludarabine 30 mg/m2/d × 5 and melphalan 140 mg/m2 × 1 (Flu-Mel140) is a commonly used reduced-intensity conditioning regimen. We hypothesized that addition of 200cGy total body irradiation (TBI) to Flu-Mel140 may improve antitumor activity and transplant outcomes. Primary objectives was overall survival (OS) at 3 years. Secondary objectives were to assess the cumulative incidences of acute and chronic GVHD, relapse-free survival (RFS), relapse rate, and nonrelapse mortality (NRM). We retrospectively evaluated outcomes of patients receiving Flu-Mel140-TBI followed by HLA-matched donor allogeneic hematopoietic stem cell transplantation (alloSCT) using peripheral blood stem cells. Eighty-one patients (median age, 58 years) underwent alloSCT between January 2008 and December 2018. Thirty-one percent of patients had a prior transplant, 32% had high or very-high disease risk index, and the donor was unrelated in 70% of patients. Grade 3 to 4 regimen-related toxicities were mucositis (37%), cardiac toxicity (17%), and renal toxicity (10%). The cumulative incidence of grade III to IV acute GVHD at day +100 was 24.7% and chronic GVHD at 1 year was 51.3%. Median follow-up for survival was 6.1 years. At 3 years, OS was 39.81%, RFS was 31.47%, and relapse rate was 30.5%. One-year NRM was 29.9%. Patients undergoing first transplantation experienced improved OS compared with second or beyond (63.08% versus 42.31%, P = .02). After adjusting for disease subtypes, age (≤55 versus 55), comorbidity index (CI), number of transplant and GVHD prophylaxis, multivariable analysis did not demonstrate any survival difference among disease subtypes. High CI (≥3) was predictive of adverse OS and NRM, whereas older age (>55 years) was associated with high NRM. Our study shows that Flu-Mel140-TBI seems feasible and provides durable disease control. Addition of TBI did not appear to improve outcomes compared to previously published reports of Flu-Mel140. Considerable NRM could result from the inclusion of patients with older age and prior transplants.
Guselkumab: First Global Approval. [2019]Guselkumab (Tremfya™) is a human monoclonal IgG1λ antibody being developed by Janssen Biotech, Inc. that has been approved in the USA as a treatment for moderate-to-severe plaque psoriasis. Guselkumab inhibits the binding of interleukin 23 (IL-23) to its cell surface receptor, disrupting the type 17 helper T cell/IL-17 pathway. This article summarizes the milestones in the development of guselkumab leading to this first approval for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
Large increments in psoralen-ultraviolet A (PUVA) therapy are unsuitable for fair-skinned individuals with psoriasis. [2019]The ideal psoralen-ultraviolet A (PUVA) regimen for chronic plaque psoriasis has yet to be established. There are four components to a PUVA regimen: the dose of psoralen, the starting dose of UVA, the frequency of treatment and the incremental UVA dose protocol. Recent studies have been directed at trying to optimize the efficacy of PUVA while minimizing acute side-effects and the risk of cutaneous carcinogenesis, believed to be independently related to the cumulative dose of UVA and the total number of treatments. The British Photodermatology Group recommends two twice-weekly PUVA regimens: one starts with 50% of the minimal phototoxic dose (MPD) and uses weekly increments of 40%, 30%, 25%, 20%, 15%, 10% and 5% of the previous dose to a maximum of 14.5 J/cm2; the other starts with a fixed dose based on skin type and uses weekly dose increments of 40%, decreasing to 20% once erythema develops. We undertook a prospective randomized controlled trial comparing these regimens in 85 Irish patients. The clearance rate with the MPD regimen was lower than with the skin type regimen, 67.5% vs. 95% (P
Brodalumab for the treatment of psoriasis. [2022]Psoriasis is a complex disease in which the alteration of the IL-23/Th17 axis appears to be crucial for its pathogenic mechanisms, and anti-IL17 agents are rapidly becoming important therapeutic tools. Brodalumab, a fully human Chinese hamster ovary cell-derived immunoglobulin G2 (IgG2) anti-IL-17RA monoclonal antibody, is currently the most-developed treatment that binds to the IL-17RA. The authors review and provide updates of efficacy and safety by several studies on brodalumab. Areas covered: A PubMed search was performed for relevant literature. Among the trials of brodalumab, the most common adverse events included nasopharyngitis, headache, upper respiratory tract infection, and arthralgia. Suicidal ideation and completed suicides had been observed in the brodalumab programme, although evidence to date was quoted as not suggesting a causal association. Expert commentary: By blocking the IL-17 receptor A, brodalumab antagonizes signaling from IL-17A, IL-17F, IL-17A/F and IL-25, and this probably contributes to the high efficacy observed in clinical trials. Considering the different therapeutic target and the potential biological implications that blocking IL-17RA instead of IL-17A might have, brodalumab may not necessarily belong to the same class that includes secukinumab and ixekizumab, but it may be classified in a distinct group.
Pharmacokinetic drug evaluation of brodalumab for the treatment of psoriasis. [2019]Psoriasis is now understood to also be under the driving influence of the IL-17/IL-23 axis, and the medical breakthrough of novel IL-17 inhibitor medications signals a paradigm shift in the way psoriatic patients are managed medically. Brodalumab, a fully human Chinese hamster ovary cell-derived immunoglobulin G2 (IgG2) anti-IL-17RA monoclonal antibody, is currently the most-developed treatment that binds to the IL-17RA. The authors review and provide updates of efficacy and safety by several studies on brodalumab. Areas covered: A PubMed search was performed for relevant literature. Among the trials of brodalumab, the most common adverse events included nasopharyngitis, headache, upper respiratory tract infection, and arthralgia. Suicidal ideation and completed suicides had been observed in the brodalumab programme, although evidence to date was quoted as not suggesting a causal association. Expert opinion: Brodalumab provides an important new therapy for management of psoriasis, because there remains a significant unmet patient need for new agents that can provide novel mechanisms of action, rapid onset of effect, improved, and sustained total skin clearance, greater compliance, and minimization of drug-specific safety concerns.
A phase 4, randomized, head-to-head trial comparing the efficacy of subcutaneous injections of brodalumab to oral administrations of fumaric acid esters in adults with moderate-to-severe plaque psoriasis (CHANGE). [2021]Brodalumab is a fully human monoclonal immunoglobulin IgG2 antibody that binds to the human IL-17 receptor subunit A and by that inhibits the biologic action of IL-17A, IL-17F, IL-17C and IL-17E. Therapy with fumaric acid esters (FAE) is a well established and widely used first-line systemic treatment for subjects with moderate-to-severe plaque psoriasis.