scholarly journals Preclinical Studies and Phase I Trial of Vactosertib in Combination with Pomalidomide in Relapsed Multiple Myeloma: A Corticosteroid-Free Approach By Targeting TGF-β Signaling Pathway

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3232-3232
Author(s):  
Ehsan Malek ◽  
Sunjin Hwang ◽  
Marcos de Lima ◽  
Paolo Caimi ◽  
Molly M Gallogly ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Protein Concentration ◽  
Plasma Cells ◽  
Single Agent ◽  
Type I ◽  
Preclinical Studies ◽  
Monoclonal Protein ◽  
Progression Of Disease ◽  
Grade Iii

Multiple Myeloma (MM) is a neoplasm of terminally differentiated plasma cells which proliferate in a permissive bone marrow environment characterized by immunosuppression and osteoclast activation. Although malignant plasma cells do not harbor any mutation in the Transforming Growth Factor-beta (TGF-β) pathway, increased TGF-β secreted by MM cells lead to impaired immune surveillance and promotion of catabolic bone remodeling allowing myeloma progression (Kyrtsonis MC et al. 1998). Here, we conducted preclinical studies in the syngeneic 5T3MM immunocompetent mouse model assessing the efficacy of vactosertib (Vacto), a TGF-β type I receptor antagonist, single agent activity as well as synergistic activity with the third generation immunomodulatory drug, pomalidomide (Pom) and a subsequent corticosteroid-free phase I study to test safety and preliminary efficacy of this combination. (NCT03143985). Methods Preclinical: Mice bearing 5T33MM cells expressing luciferase were treated with Vacto/Pom and the combination for 3 weeks, and evaluated for MM growth by bioluminescence imaging (BLI). Cellular and molecular assays were performed in human RPMI8226 and U266 as well as murine 5T33MM cells via apoptosis, real-time PCR and Western blotting. Peripheral blood monoclonal protein concentration, M-spike, was measured by ELISA. Distal femur trabecular bone structure was assessed by 3D micro-CT. Phase I: pts with relapsed MM with at least two lines of therapies enrolled on a modified Fibonacci 3 + 3 dose escalation design and received escalating dosages of Vacto, 60 mg/d, 120 mg/d and 100 mg BID and 200 mg BID in combination with standard dose of Pom (4mg) without corticosteroids. The study objectives were to assess safety, recommended phase 2 dose, and efficacy of Vacto/Pom in compared to historical control of Pom without corticosteroids (PFS-6: 20% in randomized Phase II study by Richardson et al. Blood. 2014). Vacto tablets, taken daily for 5 days followed by 2 days off, was administered in 28-day cycles, repeated for 6 cycles or until progression of disease or intolerable toxicity. There was no fasting requirement after the first two dose levels. Results: Preclinical: Vacto attenuated the growth and viability of human and murine MM cells by inducing apoptosis and inhibited TGF-β-induced activation of Smad2/3 in MM cells in vitro. In the 5T33MM preclinical model, Vacto inhibited MM progression, as single agent, as measured by peripheral blood monoclonal protein concentration and BLI before and after treatment. Vacto also prolonged survival (Figure-1), prevented weight loss and increased trabecular bone thickness (Figure-2) in mice bearing MM in compare to control. Vacto alone or combination with Pom also attenuated TGF-β activation of Smad2/3, reduced the expansion of CD11b⁺Gr-1⁺ myeloid derived suppressor cells (MDSCs) in the bone marrow, and diminished the population of Foxp3⁺ regulatory T cells in the spleen (Figure-1). Vacto showed anti-myeloma effect at level of 700-750 nM on myeloma cells from three MM pts (Figure-3). Phase I: As of July 30th 2019, 10 pts were enrolled in the study (Table-1). Three pts were refractory to bortezomib and four pts were refractory to lenalidomide. The most common non-hematologic adverse event (AE) was grade II fatigue and pain in one pt with one episode of grade III renal failure that took less than 7 days to get back to baseline, no grade IV non-hematologic AE was observed. Two pts had grade III hematologic AE, no grade IV hematologic AE. Two out of 10 patients experienced progression of disease (PFS-6: 80%) (Figure-4, 5). Conclusions: Vacto is a small molecule TGF-β type I receptor inhibitor that has shown single agent activity against myeloma in the syngeneic 5T33MM murine mouse model, in human myeloma cell lines and primary patient samples. Its effect on the tumor microenvironment is augmented in combination with Pom in the Cereblon-negative immunocompetent murine model. The phase I data shows safety of this agent in combination with Pom. The preliminary efficacy assessment is PFS-6: 80% which is higher than historical control (Richardson et al. Blood. 2014) with Pom only (PFS-6: 20%) or Pom with corticosteroids (PFS-6: 40%). Further advancement of this agent in clinical trial pipelines for MM is planned. Disclosures Malek: Amgen: Speakers Bureau; Adaptive: Consultancy; Janssen: Speakers Bureau; Medpacto: Research Funding; Sanofi: Consultancy; Takeda: Consultancy; Celgene: Consultancy. Hwang:MedPacto: Employment. Metheny:Takeda: Speakers Bureau; Incyte: Speakers Bureau. OffLabel Disclosure: Experimental therapeutics: Vactosertib

scholarly journals Preclinical Studies and a Phase I Trial of the TGF-β Receptor Inhibitor, Vactosertib (TEW-7197), in Combination with Pomalidomide in Patients with Multiple Myeloma Refractory to Bortezomib or Lenalidomide

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1962-1962 ◽  
Author(s):  
Ehsan Malek ◽  
Byung-Gyu Kim ◽  
Jason Valent ◽  
James Driscoll ◽  
Paolo Caimi ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Protein Concentration ◽  
Single Agent ◽  
Preclinical Studies ◽  
Advisory Committees ◽  
Monoclonal Protein ◽  
Progression Of Disease ◽  
Grade Iii

Abstract Multiple myeloma (MM) is characterized by the loss of critical mediators of immune surveillance and the activation of osteoclast. The transforming growth factor-beta (TGF-β) signaling pathway has been implicated in MM progression through promotion of catabolic bone remodeling, IL-6 secretion and Th17 T cell development, promoting osteolytic bone disease, immune suppression and MM progression. Here, we conducted preclinical studies in the syngeneic 5T3MM immunocompetent mouse model of MM to assess the single agent activity of vactosertib (Vacto, TEW-7197), a TGF-β type I receptor kinase inhibitor, and the potential to act synergistically with the third-generation immunomodulatory drug, pomalidomide (Pom). These data support the first clinic trial to evaluate this combination regimen in patients (pts) with MM (NCT03143985, open and recruiting). Methods Preclinical: Mice bearing 5T33MM cells expressing luciferase were treated with Vacto, Pom and the combination for 3 weeks, and evaluated for MM growth by bioluminescence imaging (BLI). Cellular and molecular assays were performed in human RPMI8226 and U266 as well as murine 5T33MM cells via apoptosis, real-time PCR and western blotting. Peripheral blood monoclonal protein concentration, M-spike, was measured by ELISA. Distal femur trabecular bone structure was assessed by 3D micro-CT. Phase I clinical trial: In this open-label study, pts with relapsed MM with at least two lines of therapies received escalating dosages of Vacto in combination with a standard dose of Pom (4 mg) without corticosteroids. The study was conducted as a modified Fibonacci 3 + 3 dose escalation design to assess safety, maximum tolerated dose, recommended phase 2 dose, and efficacy of Vacto/Pom combination in compared to historical control of Pom without corticosteroids (PFS-6: 20% in randomized Phase II study by Richardson et al. Blood. 2014). Vacto tablets are administered orally in 28-day cycles, taken once daily for 5 days followed by 2 days without treatment, repeated either for 6 cycles or until progression of disease or intolerable toxicity. Dosing was initiated at 60 mg and increased to 120 and 240 mg. Results Preclinical: Vacto attenuated the growth and viability of human and murine MM cells by inducing apoptosis and inhibited TGF-β-induced activation of Smad2/3 in MM cells in vitro. In the 5T33MM preclinical model, single agent Vacto inhibited MM progression as measured by peripheral blood monoclonal protein concentration and BLI. Vacto also prolonged survival (Figure-1), prevented weight loss and increased trabecular bone thickness (Figure-2) in mice bearing MM. Vacto either alone or in combination with Pom also attenuated TGF-β activation of Smad2/3, reduced the expansion of CD11b⁺Gr-1⁺ myeloid derived suppressor cells (MDSCs) in the bone marrow and diminished the population of Foxp3⁺ regulatory T cells in the spleen (Figure-1). Vacto showed anti-myeloma activity in cells from three MM pts (Figure-3) at 700-750 nM in vitro. Phase I: As of 01 July 2018, 5 pts were enrolled; 3 pts received 60 mg daily and 2 pts received 120 mg daily. Patient demographics include: median age of 70 years (range: 64-77); 3-5 lines of prior therapy; ISS stage II or III; two pts had high risk cytogenetics including 17p deletion; three pts were refractory to bortezomib and four pts were refractory to lenalidomide. None of five enrolled pts developed any DLT or needed Vacto dose reduction .The most non-hematologic common adverse event (AE) was grade II fatigue and pain in one pt with no grade III or IV non-hematologic AEs. No pt experienced any progression of disease (PFS-6: 100%). Figure-4 illustrates fluctuations in disease markers at each cycle interval. Two pts had grade III hematologic AE, no grad IV hematologic AE. Conclusions: Vacto has activity against myeloma in the syngeneic 5T33MM murine MM mouse model and in both human MM cell lines and primary patient MM samples. Remarkably, the effect of Vacto on the tumor microenvironment is augmented in combination with Pom in the Cereblon-negative immunocompetent 5T33MM model. The phase I data show safety of this agent in combination with Pom. The preliminary efficacy assessment is PFS-6: 100% which is higher than historical controls (Richardson et al. Blood. 2014) with Pom only (PFS-6: 20%) or Pom with corticosteroids (PFS-6:40%). Advancement of Vacto in clinical trial pipelines for MM and other malignant hematological disorders is planned. Disclosures Malek: Takeda: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau. Caimi:Kite Pharma: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees. Kim:MedPacto: Other: Founder/CEO.

Phase Ib trial of vactosertib in combination with pomalidomide in relapsed multiple myeloma: A corticosteroid-free approach by targeting TGF-β signaling pathway.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8039-8039
Author(s):  
Ehsan Malek ◽  
Sunjin Hwang ◽  
Paolo Fabrizio Caimi ◽  
Leland L. Metheny ◽  
Benjamin Kent Tomlinson ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
Immune System ◽  
Transforming Growth Factor ◽  
Single Agent ◽  
Cell Activity ◽  
Type I ◽  
Phase Ib ◽  
Progression Of Disease ◽  
Grade Iii

8039 Background: Immunosuppression and osteoclast activation are two hallmarks of the bone marrow environment in Multiple Myeloma (MM). Corticosteroids have been used historically as part of anti-myeloma regimens due to their anti-plasma cell activity, however they potentially could suppress immune system and activate osteoclast further; therefore there is an unmet need for corticosteroid-free approaches in the era of emerging anti-cancer immunotherapy modalities. There is an abundance of Transforming Growth Factor-beta (TGF-β), a crucial cytokine in suppression of immune system as well as catabolic bone remodeling, in the MM microenvironment. Vactosertib (Vacto) is a small molecule TGF-β type I receptor inhibitor that has shown single agent activity against myeloma in the syngeneic 5T33MM murine mouse model. Here, we report the phase Ib trial of Vacto in combination with pomalidomide (Pom) without any corticosteroids (NCT03143985). Methods: pts with relapsed MM with at least two lines of therapies enrolled on a 3 + 3 dose escalation design and received Vacto, 60 mg/d, 120 mg/d, 100 mg BID and 200 mg BID in combination with standard dose of Pom (4mg) without corticosteroids. The primary objectives of the study was to assess safety and recommended phase 2 dose. Vacto tablets, taken once or twice daily for 5 days followed by 2 days without treatment, is administered in 28-day cycles, until progression of disease or intolerable toxicity. Results: 15 pts were enrolled on the study (Table). The most common non-hematologic adverse event (AE) was grade II fatigue and pain in one pt, one episode of grade III renal failure that took less than 7 days to get back to baseline on another patient, sinus bradycardia that reversed to sinus rythem and an Afib that was rate controlled with beta blocerks. No grade IV non-hematologic AE was observed. Three pts had grade III hematologic AE, no grade IV hematologic AE. Three out of 15 pts experienced progression of disease (PFS-6: 80%). Conclusions: The phase Ib data shows safety of this agent in combination with Pom. The efficacy assessment (PFS-6: 80%) is higher than the historical control (PFS-6: 20% in randomized Phase II study by Richardson et al. Blood. 2014) with Pom only (PFS-6: 20%) or Pom with corticosteroids (PFS-6: 40%). Further advancement of this agent in clinical trial pipelines for MM is planned. Clinical trial information: NCT03143985. [Table: see text]

A Phase I Study of CHR-2797, an Orally Active Aminopeptidase Inhibitor in Elderly and/or Treatment Refractory Patients with Acute Myeloid Leukemia or Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 443-443 ◽  
Author(s):  
Faith Davies ◽  
Gert Ossenkoppele ◽  
Pierre Zachee ◽  
Richard Noppeney ◽  
Alan Burnett ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Active Metabolite ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Once Daily ◽  
Grade Iii ◽  
Acute Myeloid

Abstract Background. CHR-2797 is a novel, orally bioavailable agent which displays potent, tumor cell-selective, anti-proliferative properties. It is an inhibitor of Zn++-dependent aminopeptidases and generates signs of amino acid deprivation in sensitive cells, decreased protein synthesis and an increase in the level of the pro-apoptotic protein, NOXA. CHR-79888 is an active metabolite of CHR-2797. Methods. This was an open label, single agent, dose escalating phase I salvage study to assess tolerance, MTD/DLT, activity, and pharmacokinetics of CHR-2797 in patients with hematological malignancies. Elderly patients and/or relapsed patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and multiple myeloma (MM) were eligible. Patients were treated with escalating once daily doses (60–180 mg) for up to 84 days or until progressive disease (PD). Clinical responses were assessed by monthly bone marrow aspirates in AML/MDS patients and by M-protein levels in MM patients. Results. Sixteen adults (4 women, 12 men) of median age 70 yrs, (range 45–84 yrs) were accrued between May 2006 and Jan 2007: 13 patients with AML, 1 with MDS, and 2 with MM. Thirteen patients finished the dose finding phase of 28 days and 6 patients continued for at least 84 days. CHR-2797 was well tolerated and, except for one patient with grade III ALT elevation, no grade III/IV drug related non-hematological toxicity was observed during the first 28 days of treatment. Two patients on 180 mg developed DLT that was considered drug related: >75 percent reduction in platelet count. CHR-2797 had no influence on hemoglobin or neutrophils in this trial. Overall the most frequently reported adverse events were thrombocytopenia (6.7%), diarrhea (4.5%), dizziness (3.9%), and fatigue (3.9%). Five AML patients died in the first 3 months of the trial or within 4 weeks of discontinuing CHR-2797: 3 due to disease progression and 2 following a MI (not related to drug). Bone marrow studies revealed complete responses (< 5% blasts in bone marrow) in 3/12 AML patients after 1–3 months of therapy (60 and 130mg), one of which was also a cytogenetic response. One of the 2 responding patients on 130 mg was evaluated as a CRp at 3 months; this patient was in remission for 3 months following platelet recovery after the drug was stopped. One further AML patient (60 mg) became completely transfusion independent and remained so for 6 weeks. Good exposure to CHR-2797, including levels of the active metabolite CHR-79888 has been observed on days 1 and 28 with a terminal half life (for 79888) of 8– 11 hours. Conclusions. Oral once daily CHR-2797 in AML/MDS/MM patients with adverse prognostic risk was well tolerated. MTD for maintenance therapy was reached at 180 mg. Single agent CHR-2797 therapy showed encouraging clinical activity (incl. 3/12 CRs) in these elderly and poor risk AML patients who were able to continue therapy for at least 28 days. Because of the favorable results a phase II study with CHR-2797 in advanced AML is currently in progress.

Phase I Trial of CCI-779 (Temsirolimus) and Weekly Bortezomib in Relapsed and/or Refractory Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3696-3696 ◽  
Author(s):  
Irene M. Ghobrial ◽  
Nikhil Munshi ◽  
Robert Schlossman ◽  
Stacey Chuma ◽  
Renee Leduc ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Peripheral Neuropathy ◽  
Phase I ◽  
Median Time ◽  
Single Agent ◽  
Mtor Inhibitors ◽  
Hematologic Toxicity ◽  
Cell Transplant ◽  
Dose Escalation Study ◽  
Progression Of Disease

Abstract BACKGROUND: Preclinical studies have demonstrated activity of the combination of mTOR inhibitors and bortezomib in Multiple Myeloma (MM). Single agent mTOR inhibitors (including CCI-779) have shown modest activity in MM. The objective of this phase I dose-escalation study was aimed to determine the maximum tolerated dose (MTD) as well as the activity of the combination of CCI-779 (Wyeth Pharmaceutical, PA) and bortezomib (Millennium Pharmaceutical, MA) in patients with relapsed and/or relapsed, refractory MM. METHODS: Four cohorts (3 patients each) were planned, with dosing of bortezomib 1.3 or 1.6mg/m2 (days 1, 8, 15 and 22) every 35 days (1 cycle) and CCI-779 15 or 25 mg IV (days 1, 8, 15, 22 and 29) every cycle. Dexamethasone was not permitted during therapy. NCI CTCAE v3.0 was used for toxicity assessment; Dose limiting toxicity (DLT) was defined as any grade (G) 3 or greater non-hematologic toxicity related to therapy, G4 neutropenia for 7 d and/or neutropenic fever, or platelets <10,000/mm3 on >1 occasion despite transfusion, inability to receive day 1 dose for cycle 2 due to toxicity. Response was assessed by modified EBMT criteria. Prior therapy with bortezomib or CCI-779 was allowed. Patients remained on therapy until progression of disease or intolerance. RESULTS: Twenty patients (13 men and 7 women) have been treated to date, of these 5 were on cohort 3 and 9 on cohort 4. The median age was 58 yrs (range: 48–81), and median number of prior therapies was 5 (range: 1–10), including prior stem cell transplant with autologous, or allogeneic transplant, bortezomib, lenalidomide, thalidomide, and combination chemotherapy. All of the patients had received prior bortezomib therapy except for one patient. One DLT was observed in cohort 4 (death due to sepsis and septic shock grade 5, possibly related to therapy and underlying myeloma). Cohort 4 was expanded and no further DLTs were observed. MTD was therefore declared at CCI-779 of 25 mg and bortezomib of 1.6mg/m2. Grade (G) 3 and 4 related toxicities included thrombocytopenia (G3 in 35%, G4 in 25%) leucopenia and neutropenia G3 in 25% with no G4 toxicity, G3 anemia in 15%, and nausea, vomiting, viral infection, hyponatremia, pneumonia, hyperglycemia, mucositis, fatigue, and renal insufficiency in 2% of patients. No significant (G2 to G4) peripheral neuropathy has been seen thus far. No anticoagulant prophylaxis has been required, and no DVTs have occurred. The median time of follow up is 6 months (1–13 months). Response was assessed after completion of 2 cycles of therapy. In 15 evaluable patients, the overall response rate (CR+PR+MR) was 33% (5 patients), including 1nCR and 4 MR. The median time of therapy of patients who achieved response was 8 months (2–12 months). All responses occurred in patients who have received prior bortezomib. Six patients had stable disease for a median of 7 months (6–11 months), and 4 patients showed progression of disease (at 3–5 months post initiation of therapy). Responses occurred in the early cohorts indicating activity of these agents even at lower doses. Conclusions: The combination of CCI-779 25 mg and weekly bortezomib 1.6mg/m2 weekly is active and well tolerated, and minimal peripheral neuropathy to date. The ORR of 33% in heavily pretreated patients with MM, including prior bortezomib therapy, is encouraging. The phase II trial using the MTD of this combination is currently being initiated and enrollment is ongoing.

Phase I Study of 30-Minute Infusion of Carfilzomib As Single Agent or in Combination With Low-Dose Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma

2015 ◽  
Vol 33 (7) ◽  
pp. 732-739 ◽  
Author(s):  
Kyriakos P. Papadopoulos ◽  
David S. Siegel ◽  
David H. Vesole ◽  
Peter Lee ◽  
Steven T. Rosen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Concentration ◽  
Phase I ◽  
Phase I Study ◽  
Low Dose ◽  
Single Agent ◽  
Phase Iii ◽  
Maximum Plasma ◽  
Irreversible Inhibitor ◽  
Refractory Multiple Myeloma

Purpose Carfilzomib is an irreversible inhibitor of the constitutive proteasome and immunoproteasome. This phase I study evaluated the maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of carfilzomib administered as a 30-minute intravenous (IV) infusion. Safety and efficacy of carfilzomib as a single agent or in combination with low-dose dexamethasone were assessed. Patients and Methods Patients with relapsed and/or refractory multiple myeloma (MM) were administered single-agent carfilzomib on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Cycle one day 1 and 2 doses were 20 mg/m2, followed thereafter by dose escalation to 36, 45, 56, or 70 mg/m2. Additionally, carfilzomib was combined with low-dose dexamethasone (40 mg/wk). Results Thirty-three patients were treated with single-agent carfilzomib. Dose-limiting toxicities in two patients at 70 mg/m2 were renal tubular necrosis and proteinuria (both grade 3). The MTD was 56 mg/m2. Nausea (51.5%), fatigue (51.5%), pyrexia (42.4%), and dyspnea and thrombocytopenia (each 39.4%) were the most common treatment-related toxicities. Overall response rate (ORR) was 50% (56-mg/m2 cohort). Increasing carfilzomib dosing from 20 to 56 mg/m2 resulted in higher area under the plasma concentration-time curve from time zero to last sampling and maximum plasma concentration exposure with short half-life (range, 0.837 to 1.21 hours) and dose-dependent inhibition of proteasome chymotrypsin-like activity. In 22 patients treated with 45 or 56 mg/m2 of carfilzomib plus low-dose dexamethasone, the ORR was 55% with a safety profile comparable to that of single-agent carfilzomib. Conclusion Carfilzomib administered as a 30-minute IV infusion at 56 mg/m2 (as single agent or with low-dose dexamethasone) was generally well tolerated and highly active in patients with relapsed and/or refractory MM. These data have provided the basis for the phase III randomized, multicenter trial ENDEAVOR.

scholarly journals Current approaches to supportive care in multiple myeloma

2011 ◽  
Vol 139 (suppl. 2) ◽  
pp. 123-128
Author(s):  
Nenad Govedarovic ◽  
Tomislav Vukicevic
Keyword(s):  
Multiple Myeloma ◽  
Chronic Condition ◽  
Malignant Disease ◽  
Plasma Cells ◽  
Supportive Therapy ◽  
Bone Destruction ◽  
Monoclonal Protein ◽  
Blood Disease ◽  
Skeletal Disease

Myeloma multiplex is a malignant blood disease in which monoclonal expansion of malignant plasma cells occurs, together with hyperproduction of monoclonal protein,as well as impairment of normal haematopoiesis. Specific features of myeloma include bone destruction, renal failure and immunologic deficiency which decreases the overall quality of the patient?s life. Thus, prevention and supportive therapy of skeletal disease, anaemia, pain, nausea, infection and hypercalcemia, represent the essential part of therapy in myeloma patients. Improvements achieved in the specific haematological treatment, including supportive measures of complications of multiple myeloma, previously defined as incurable malignant disease, results in the improvement of the overall survival and the quality of life of these patients, thus qualifing multiple myeloma into a chronic condition.

scholarly journals Quantitative PK/PD Prediction of the Efficacious and Safe Dose Ranges of the LMP7 Inhibitor M3258 for Phase I Application in Relapsed/Refractory Multiple Myeloma Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5582-5582
Author(s):  
Florian Lignet ◽  
Christina Esdar ◽  
Manja Friese-Hamim ◽  
Andreas Becker ◽  
Elise Drouin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research And Development ◽  
Phase I ◽  
Dose Escalation ◽  
Single Agent ◽  
Proteasome Inhibitors ◽  
Refractory Multiple Myeloma ◽  
Oral Application ◽  
Development Institute ◽  
Safe Dose

M3258 is an orally bioavailable, potent, selective, reversible inhibitor of the large multifunctional peptidase 7 (LMP7, β5i, PSMB8) proteolytic subunit of the immunoproteasome; a crucial component of the cellular protein degradation machinery, which is highly expressed in malignant hematopoietic cells including multiple myeloma. M3258 was previously shown to deliver strong in vivo preclinical efficacy in multiple myeloma xenograft models, as well as a more benign non-clinical safety profile compared to approved pan-proteasome inhibitors, exemplified by a lack of effects on the central and peripheral nervous systems and cardiac and respiratory organs. Here we describe preclinical PK/PD and PK/efficacy modelling which led to a prediction of the PK profile, and the efficacious and safe dose ranges of M3258 in human which were used to guide the design of the phase I dose-escalation trial of M3258 in >3 line relapsed/refractory multiple myeloma (RRMM) patients. Mouse, rat, dog and monkey PK, plasma protein binding and intrinsic clearance data were used to estimate a half-life of approximately 6 hours for M3258 in human. The human total clearance and volume of distribution for M3258 were predicted to be 0.033 L/h/kg and 0.28 L/kg, respectively, whilst oral bioavailability was estimated to be above 80%. LMP7 proteolytic activity was assessed as a PD readout in human multiple myeloma tumor cells xenografted to mice as well as in dog peripheral blood mononuclear cells (PBMCs). A strong PK/PD relationship was observed for M3258 across both species. LMP7 inhibition by M3258 also correlated strongly with anti-tumor efficacy in multiple myeloma xenografts, with maximal efficacy observed at M3258 exposure delivering sustained inhibition of tumor LMP7 activity. Quantitative PK/PD/efficacy modeling predicted the biologically efficacious dose (BED) of M3258 upon oral application to be between 10 - 90 mg daily in human. By incorporating data from nonclinical safety studies, these data suggest an attractive human PK profile of M3258, enabling oral application, as well as an improved human therapeutic index compared to approved pan-proteasome inhibitors. M3258 is being investigated in a phase I, first-in-man, 2-part, open label clinical study designed to determine the safety, tolerability, PK, PD and early signs of efficacy of M3258 as a single agent (dose-escalation) and co-administered with dexamethasone (dose-expansion) in participants with RRMM whose disease has progressed following > 3 prior lines of therapy and for whom no effective standard therapy exists. Integration of these data will guide the selection of the BED for potential further clinical development of M3258. Disclosures Lignet: Merck Healthcare KGaA: Employment. Esdar:Merck Healthcare KGaA: Employment. Friese-Hamim:Merck Healthcare KGaA: Employment. Becker:Merck Healthcare KGaA: Employment, Other: Holding shares with a value below 1000-USD. Drouin:EMD Serono Research and Development Institute: Employment. El Bawab:Merck Healthcare KGaA: Employment. Goodstal:EMD Serono Research and Development Institute: Employment. Gimmi:Merck Healthcare KGaA: Employment. Haselmayer:Merck Healthcare KGaA: Employment. Jährling:Merck Healthcare KGaA: Employment. Sanderson:Merck Healthcare KGaA: Employment. Sloot:Merck Healthcare KGaA: Employment. Stinchi:Merck Healthcare KGaA: Employment. Victor:Merck Healthcare KGaA: Employment. Walter:Merck Healthcare KGaA: Employment. Rohdich:Merck Healthcare KGaA: Employment.

scholarly journals Phase I and Pharmacologic Study of SNS-032, a Potent and Selective Cdk2, 7, and 9 Inhibitor, in Patients With Advanced Chronic Lymphocytic Leukemia and Multiple Myeloma

2010 ◽  
Vol 28 (18) ◽  
pp. 3015-3022 ◽  
Author(s):  
Wei-Gang Tong ◽  
Rong Chen ◽  
William Plunkett ◽  
David Siegel ◽  
Rajni Sinha ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Clinical Efficacy ◽  
Stable Disease ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Dose Escalation Study

Purpose SNS-032 is a highly selective and potent inhibitor of cyclin-dependent kinases (Cdks) 2, 7, and 9, with in vitro growth inhibitory effects and ability to induce apoptosis in malignant B cells. A phase I dose-escalation study of SNS-032 was conducted to evaluate safety, pharmacokinetics, biomarkers of mechanism-based pharmacodynamic (PD) activity, and clinical efficacy. Patients and Methods Parallel cohorts of previously treated patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) received SNS-032 as a loading dose followed by 6-hour infusion weekly for 3 weeks of each 4-week course. Results There were 19 patients with CLL and 18 with MM treated. Tumor lysis syndrome was the dose-limiting toxicity (DLT) for CLL, the maximum-tolerated dose (MTD) was 75 mg/m2, and the most frequent grade 3 to 4 toxicity was myelosuppression. One patient with CLL had more than 50% reduction in measurable disease without improvement in hematologic parameters. Another patient with low tumor burden had stable disease for four courses. For patients with MM, no DLT was observed and MTD was not identified at up to 75 mg/m2, owing to early study closure. Two patients with MM had stable disease and one had normalization of spleen size with treatment. Biomarker analyses demonstrated mechanism-based PD activity with inhibition of Cdk7 and Cdk9, decreases in Mcl-1 and XIAP expression level, and associated CLL cell apoptosis. Conclusion SNS-032 demonstrated mechanism-based target modulation and limited clinical activity in heavily pretreated patients with CLL and MM. Further single-agent, PD-based, dose and schedule modification is warranted to maximize clinical efficacy.

Altered Kinetics and Localization of MMSET Variants Suggests That RE-IIBP Overexpression Is a Unifying Event in t(4;14)(p16;q32) Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 75-75 ◽  
Author(s):  
Jonathan J. Keats ◽  
Christopher A. Maxwell ◽  
Tony Reiman ◽  
Brian J. Taylor ◽  
Michael J. Mant ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Translation Initiation ◽  
Plasma Cells ◽  
Initiation Site ◽  
Protein Product ◽  
Full Length ◽  
Translation Initiation Site ◽  
Type I ◽  
Alternative Translation Initiation ◽  
Alternative Translation

Abstract Translocations involving the IgH locus are common genetic events in multiple myeloma (MM). A number of recurrent IgH translocations exist with t(11;14)(q13;q32) and t(4;14)(p16;q32) being the most common. These translocations predict for differential clinical outcomes, good versus poor, respectively. We have shown that ~70% of t(4;14) POS patients express the initially proposed target gene FGFR3. However, the t(4;14)POS/FGFR3NEG group of patients still fare poorly (P=0.01). Therefore, either the transformation event associated with t(4;14) is multifactorial or independent of FGFR3. The loss of FGFR3 expression is associated with the loss of der(14). However, der(4) is detectable in all t(4;14)POS patients at diagnosis and relapse, suggesting that it is biologically and clinically relevant. The der(4) chromosome is thought to result in the overexpression of MMSET. The genomic breakpoints associated with t(4;14) occur in the 5′ end of the MMSET locus. In 70% of patients (MB4-1), the breakpoints maintain the full length open reading frame of MMSET. In the remaining 30% (MB4-2 & MB4-3), the breakpoints occur downstream of the proper translation initiation site. Two principle transcripts originate from the MMSET gene. The first transcript initiates in the beginning of the MMSET locus and, as a result of alternative splicing of exon 12, produces either MMSET I or MMSET II. The second transcript initiates upstream of exon 10 and uses an alternative translation initiation site to produces RE-IIBP. MMSET I and II transcripts, produced by each breakpoint variant, and the RE-IIBP transcript, produced in all patients irrespective of breakpoint type, were cloned. Transcripts were C-terminally tagged with GFP and transiently transfected into HeLa cells. Anti-GFP immunoblots showed that all transcripts produced a protein product, even the MB4-2 and MB4-3 variants that utilize alternative translation initiation sites in exon 4 and 6, respectively. The wildtype/MB4-1 MMSET I and II constructs localized to the nucleus and were excluded from nucleoli. MMSET II is almost exclusively associated with chromatin while MMSET I localized diffusely. RE-IIBP localized primarily in cytoplasmic foci and to nucleoli. Unlike the full length MMSET proteins, the MB4-2/MB4-3 constructs localized to the nucleus but also localized in nucleoli. To determine if the N-terminus regulates the nuclear localization pattern, we cloned the N-terminal portion of MMSET, which is lost in the MB4-2 transcripts. As this construct localized to the nucleus and was excluded from nucleoli, therefore a domain required for the proper localization of MMSET is lost in the MB4-2/MB4-3 variants. Kinetic analysis of MMSET variants localized to the nucleoplasm shows that the association of MMSET II with chromatin is very stable, t1/2 130 sec, while the type II MB4-2 and MB4-3 breakpoint variants have reduced kinetics, t1/2 19 and 12 sec, respectively, suggesting a decreased stability of association. The reduction in kinetics is also seen in the type I variants. We verified the overexpression of RE-IIBP by quantitative RT-PCR on a panel of purified plasma cells and unpurified BMMC. RE-IIBP was overexpressed in t(4;14)POS patients, P=0.0009 and P=0.00006, respectively, making it the only overexpressed protein without altered function in all t(4;14)POS patients irrespective of FGFR3 expression or breakpoint type. Therefore, RE-IIBP may be of central importance to the poor outcome of t(4;14)POS MM patients.

A Phase I/II Study of Bortezomib and Low Dose Intravenous Melphalan (BM) for Relapsed Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2555-2555 ◽  
Author(s):  
Rakesh Popat ◽  
Heather E. Oakervee ◽  
Nicola Foot ◽  
Samir Agrawal ◽  
Patricia Smith ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Progressive Disease ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Median Number ◽  
Overall Response ◽  
Grade 3 ◽  
Number Of Cycles

Abstract Background: Bortezomib as a single agent has known efficacy in the treatment of relapsed multiple myeloma. The overall response rate (CR+PR+MR) was 35% in the SUMMIT study and 46% in the APEX study. In-vitro studies including our own have demonstrated potent synergy with other chemotherapeutic agents such as melphalan. It therefore follows that responses to bortezomib may be further improved by the combination of such drugs. Aims: The primary objectives of this Phase I/II study was to assess the safety, tolerability and response rates in patients with relapsed multiple myeloma; secondary objectives being time to progression (TTP) and overall surival (OS). Methods: This was a multi-centre, non-randomised trial for patients with relapsed myeloma. Patients received bortezomib 1.3mg/m2 on days 1,4,8 and 11 of each 28 day cycle with melphalan on day 2 at increasing dose levels. This was initially at 10mg/m2, but due to cytopenias subsequently at 2.5 and 5mg/m2 (levels 1a, 1 and 2) and we plan to escalate to 7.5mg/m2. Up to 8 cycles were given with dexamethasone added for stable or progressive disease after 4 or 2 cycles respectively. Responses were determined by EBMT criteria. Results: To date, 18 patients have been enrolled (12 male 6 female; median age 60 [range 44–73]; median number of prior therapies 3 [range 1–5] of which 17 have had at least one autologous stem cell procedure with high dose melphalan; 10 prior thalidomide and 2 prior bortezomib). 12 patients received melphalan at 10mg/m2 but due to unacceptable delays predominantly due to thrombocytopaenia, subsequent treatment levels commenced at 2.5mg/m2. The median number of cycles completed thus far is 4 (range 0–8) and of the 16 evaluable, the overall response rate (CR+PR+MR) across all treatment levels was 50% rising to 75% following the addition of dexamethasone as per protocol. At level 1a (melphalan 10mg/m2 ,N=12, median number of cycles completed =5) the best responses (with dexamethasone as indicated) were: 1CR, 1 VGPR, 5 PR, 2 MR; at level 1 (melphalan 2.5mg/m2, N=4) 1 PR, 2 MR (after 2 cycles only). The median time to any response was 1 cycle (range 1–3 ). Three patients have progressive disease, but the median TTP and OS have not yet been reached (median follow-up 3 months). Non-haematological toxicities have been modest with 7 SAEs reported of which only 1 was possibly drug related (myocardial infarction), and 4 episodes of Grade 3 neuropathy (2 resulting in study withdrawal). The commonest grade 3–4 haematological toxicity was thrombocytopaenia (N=10) complicated by bleeding in one patient, followed by neutropenia (N=6). Summary: The combination of bortezomib and intravenous melphalan can be given safely to patients with relapsed multiple myeloma and dose escalation is ongoing. Myelosupression was the commonest grade 3–4 adverse event. A response rate of 50% was seen, which was further improved to 75% with the addition of dexamethasone. This combination may therefore result in higher responses than single agent bortezomib in heavily pretreated patients.

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