Relapsed Multiple Myeloma

Hematology ◽  
2010 ◽  
Vol 2010 (1) ◽  
pp. 303-309 ◽  
Author(s):  
Sagar Lonial
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Phase 1 ◽  
Treatment Options ◽  
Single Agent ◽  
Great Promise ◽  
New Agents ◽  
Ongoing Work ◽  
The Many

Abstract Advances in treatment options for patients with multiple myeloma have made a significant impact on the overall survival of patients and have helped achieve levels of response and duration of remission previously not achievable with standard chemotherapy-based approaches. These improvements are due, in large part, to the development of the novel agents thalidomide, bortezomib, and lenalidomide, each of which has substantial single-agent activity. In addition, a large number of second-generation agents are also in clinical development, such that the repertoire of available treatment options continues to expand. To better interpret clinical trials performed in the relapsed setting, it is important that definitions of relapse categories are used to help better pinpoint the specific benefit for a given therapy, especially in the combination therapy setting as it aids in determining if ongoing work should be continued or abandoned for a given new agent. Insights from preclinical modeling and in vitro work have identified several new combinations, new targets and second- or third-generation versions of existing targets that hold great promise in the setting of relapsed myeloma. Combinations of thalidomide, bortezomib, and lenalidomide with conventional agents or among each other have resulted in enhanced response rates and efficacy. Clinical trials of agents such as carfilzomib, pomalidomide, vorinostat, panobinostat, and elotuzomab are just a few of the many exciting new compounds that are being tested in phase 1 and phase 2 clinical trials for relapsed patients. Further clinical and translational testing are critical to better understanding how best to combine these new agents, as well as identifying patient populations that may best benefit from treatment with these developing new agents.

scholarly journals A Phase 1/2 Trial of Pomalidomide, Dexamethasone and Pegylated Liposomal Doxorubicin for Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4774-4774
Author(s):  
James R. Berenson ◽  
Laura V. Stampleman ◽  
Alberto Bessudo ◽  
Peter J. Rosen ◽  
Leonard M Klein ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Progressive Disease ◽  
Liposomal Doxorubicin ◽  
Phase 1 ◽  
Single Agent ◽  
Pegylated Liposomal Doxorubicin ◽  
Great Promise ◽  
Phase 2 ◽  
Grade 3

Abstract Background Immunomodulatory drugs (IMiD), such as thalidomide and lenalidomide (LEN) and its newest derivative pomalidomide (POM), have shown great promise for the treatment of multiple myeloma (MM) patients (pts). POM has in vitro anti-MM potency and has shown efficacy for the treatment of relapsed/refractory (RR) MM pts. POM with dexamethasone (DEX) induces responses even for MM pts who are refractory to bortezomib (BORT) and LEN (Richardson et al, 2012). Pegylated liposomal doxorubicin (PLD) with BORT is FDA-approved for the treatment of MM pts who have received one prior therapy not containing BORT. The combination of PLD and LEN or thalidomide has shown efficacy for both RR and frontline MM pts (Offidani et al, 2006; 2007). We have also demonstrated that both the efficacy and tolerability of LEN in combination with DEX, PLD and BORT (DVD-R) may be improved by changing the doses and schedules of these drugs (Berenson et al, 2012). Based on these results, we hypothesized that the combination of POM, DEX and PLD would be effective for the treatment of RRMM pts. Thus, we conducted the first study investigating the safety and efficacy of POM in combination with intravenous (IV) DEX and PLD as a phase 1/2 trial using a modified dose, schedule and longer 28-day cycles for pts with RRMM. Methods The phase 1 portion enrolled MM pts w/ progressive disease whereas those enrolled in phase 2 also had to be refractory to LEN (single-agent or in combination), as demonstrated by progressive disease while receiving their last LEN-containing regimen or relapsed within 8 weeks of their last dose of this IMiD. Pts who have previously received POM treatment were ineligible. In the phase 1 portion, POM was administered at 2, 3 or 4 mg daily in three cohorts on days 1-21 of a 28-day cycle and DEX (40 mg) and PLD (5 mg/m2) were fixed and given intravenously on days 1, 4, 8, and 11. Results As of June 20th, 2014, 48 pts were enrolled in the trial and a total of 47 pts had received study drug. Pts had received a median of 4 prior treatments (range 1-18), with a median of 2 prior IMiD-containing regimens (range, 0-8). Fifty-three percent of the pts had received a prior PLD-containing regimen and 21% had received a prior IMiD and PLD combination treatment. Among all enrolled pts, 40 pts discontinued treatment and seven remain active. Pts completed a median of 3 cycles (range: 1-8), with a median follow-up time of 5.4 months (range: 0-22). During the phase 1 portion of the trial, the maximum tolerated dose (MTD) of POM was established at 4 mg. Enrollment of pts into the phase 2 portion of the trial began at the MTD. However, neutropenia ≥ grade 3 was observed at this dose in 10/17 (58.8%) phase 2 pts; and, as a result, the protocol was amended so that the MTD was lowered to 3 mg for all pts subsequently enrolled. Among the 36 pts enrolled in phase 2, 78% percent were refractory to LEN and steroids with or without other agents and 47% had previously received PLD. A median of 2 cycles (range, 1 to 8) were administered among the pts enrolled in phase 2. Thirty-five pts were evaluable for response as one pt was active but had not yet had any post-baseline disease assessments. Among all pts enrolled in phase 2, the overall response rate (ORR) and clinical benefit rate (CBR) were 29% and 49%, respectively, with 6 pts (17%) showing stable disease and 12 pts (34%) demonstrating progressive disease. For all pts enrolled in phase 2, the median follow-up time was 4.7 months (range 0-12) and the median PFS was 5.3 months. ORR and CBR for pts in the phase 2 were higher among pts receiving POM at 3 mg (32% and 58%, respectively) than among pts receiving POM at 4 mg (25% and 37%, respectively). Pts receiving the 4 mg dose of POM experienced more toxicities resulting in discontinuations, which likely explains the lower ORR and CBR observed among pts receiving this POM dose. Common ≥ grade 3 adverse events observed throughout the trial were neutropenia (21 pts; 44.7%), lymphopenia (10 pts; 21.3%), and hyponatremia (4 pts; 8.5%). One pt died of grade 5 sepsis. Conclusions This phase 1/2 trial is the first evaluating POM with PLD and DEX and demonstrates that the combination of POM at 3 mg, PLD and DEX using a modified 28-day cycle schedule is safe and effective for the treatment of MM pts refractory to LEN. Disclosures Berenson: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Swift:Celgene: Consultancy, Honoraria. Vescio:Celgene: Honoraria.

scholarly journals STAT3: A Promising Therapeutic Target in Multiple Myeloma

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 731 ◽  
Author(s):  
Phyllis S. Y. Chong ◽  
Wee-Joo Chng ◽  
Sanjay de Mel
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Treatment Options ◽  
Treatment Resistance ◽  
Promising Therapeutic Target ◽  
Src Homology ◽  
Phosphatase Of Regenerating Liver ◽  
Microrna Dysregulation ◽  
Transcription 3

Multiple myeloma (MM) is an incurable plasma cell malignancy for which novel treatment options are required. Signal Transducer and Activator of Transcription 3 (STAT3) overexpression in MM appears to be mediated by a variety of factors including interleukin-6 signaling and downregulation of Src homology phosphatase-1 (SHP-1). STAT3 overexpression in MM is associated with an adverse prognosis and may play a role in microenvironment-dependent treatment resistance. In addition to its pro-proliferative role, STAT3 upregulates anti-apoptotic proteins and leads to microRNA dysregulation in MM. Phosphatase of regenerating liver 3 (PRL-3) is an oncogenic phosphatase which is upregulated by STAT3. PRL-3 itself promotes STAT-3 phosphorylation resulting in a positive feedback loop. PRL-3 is overexpressed in a subset of MM patients and may cooperate with STAT3 to promote survival of MM cells. Indirectly targeting STAT3 via JAK (janus associated kinase) inhibition has shown promise in early clinical trials. Specific inhibitors of STAT3 showed in vitro efficacy but have failed in clinical trials while several STAT3 inhibitors derived from herbs have been shown to induce apoptosis of MM cells in vitro. Optimising the pharmacokinetic profiles of novel STAT3 inhibitors and identifying how best to combine these agents with existing anti-myeloma therapy are key questions to be addressed in future clinical trials.

A Phase 1 Trial of Lenalidomide (REVLIMID®) with Bortezomib (VELCADE®) in Relapsed and Refractory Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 365-365 ◽  
Author(s):  
Paul Richardson ◽  
R. Schlossman ◽  
N. Munshi ◽  
D. Avigan ◽  
S. Jagannath ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Median Number ◽  
Significant Treatment ◽  
Prior Therapy ◽  
Best Response ◽  
Grade 3

Abstract Introduction: Bortezomib and lenalidomide are active agents in multiple myeloma (MM), and preclinical data showing additive activity in MM in vitro suggest that enhanced clinical benefit may be derived from combining the two drugs. Bortezomib is approved in MM patients (pts) who have received at least one prior therapy in both the US and EU. Lenalidomide has produced durable responses in the relapsed and refractory MM setting, including in those who received prior bortezomib. Toxicities of bortezomib and lenalidomide do not overlap unfavorably. These observations suggest that this regimen, compared with either agent alone, may provide better clinical anti-MM activity. In phase 1 trials, the maximum tolerated doses (MTD) of single-agent bortezomib and lenalidomide were 1.3 mg/m2 (IV bolus twice weekly) and 25 mg/d (PO days 1–21 of a 28–day cycle), respectively. The objective of this phase 1 dose-escalation trial was to determine the MTD and activity of this combination in pts with relapsed and/or refractory MM. Methods: Eight 3-pt cohorts were planned with bortezomib 1.0 or 1.3 mg/m2 and lenalidomide 5, 10, 15, or 20 mg/day. Pts received bortezomib on days 1, 4, 8, and 11 and lenalidomide on days 1–14 of a 21-day cycle. Dexamethasone 20 mg orally could be added on days 1, 2, 4, 5, 8, 9 and 11, 12 in the event of PD. Toxicity was assessed using NCI-CTC, version 3.0. Dose-limiting toxicity (DLT) was defined as grade ≥ 3 nonhematologic toxicity, grade 4 neutropenia lasting ≥ 5 days and/or neutropenic fever, or a platelet count ≤ 10,000 on > 1 occasion despite transfusion. Modified EBMT criteria were used to assess response. Results: Nineteen pts with MM have been enrolled to date to cohorts 1–5, including 8 with relapsed and 11 with relapsed and refractory disease. Median number of prior therapies was 4 (range, 1–9). Twelve pts had prior SCT; 17 had received thalidomide, 9 bortezomib, 2 lenalidomide. With a median of 7 cycles completed (range, 2–16), pts have received bortezomib 1.0–1.3 mg/m2 and lenalidomide 5–15 mg/d. Two pts with rapid disease progression were not evaluable and were removed from study within the first cycle. One DLT was observed (cohort 4, grade 3 hyponatremia). To date, doses of study drugs were reduced in 6 pts beyond cycle 3. Bortezomib was reduced for thrombocytopenia [n = 3] and hypotension [n = 1] and lenalidomide was reduced for neutropenia [n = 1] and fatigue [n = 1]. No significant treatment-emergent PN has been seen. Responses by cohort are shown in the table, and of 17 evaluable pts, 10 (59%) achieved CR + PR. Conclusions: In heavily treated pts with relapsed and/or refractory MM, the combination of bortezomib and lenalidomide has been well tolerated and has demonstrated very promising activity, even in pts who had previously received either agent alone. Dose escalation is continuing until MTD is reached. Phase II evaluation of this regimen is planned both in relapsed and/or refractory and in newly diagnosed MM. Cohort Bortezomib, mg/m2 Lenalidomide, mg Best Response NE = not evaluable. 1 1.0 5 2 PR, 1 MR 2 1.3 5 1 CR, 2 PR 3 1.0 10 1 nCR, 2 PR, 1 NE 4 1.3 10 2 PR, 2 MR, 1 SD, 1 PD 5 1.0 15 2 SD, 1 NE

Pomalidomide, Dexamethasone and Pegylated Liposomal Doxorubicin For Patients With Relapsed/Refractory Multiple Myeloma: Results From a Phase 1/2 Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3218-3218 ◽  
Author(s):  
James R. Berenson ◽  
James D. Hilger ◽  
Leonard Klein ◽  
Alberto Bessudo ◽  
Peter J. Rosen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Progressive Disease ◽  
Liposomal Doxorubicin ◽  
Phase 1 ◽  
Pegylated Liposomal Doxorubicin ◽  
Great Promise ◽  
Phase 2 ◽  
Effective Treatment Option ◽  
Recent Trial

Abstract Background Thalidomide and its immunomodulatory drug (IMiD) derivatives such as lenalidomide (LEN) have shown great promise as treatment options for multiple myeloma (MM) patients (pts). Pomalidomide (POM) is a newer IMiD with high in vitro anti-MM potency that has shown promise as an effective treatment option for relapsed/refractory (R/R) MM pts. Recent data has shown POM to be effective in combination with dexamethasone (DEX), even for patients who are refractory to bortezomib and lenalidomide (Richardson et al, 2012). It has been demonstrated that the addition of pegylated liposomal doxorubicin (PLD) to lenalidomide and thalidomide is effective for both R/R and frontline MM pts (Offidani et al, 2006; 2007). Our recent trial evaluating lenalidomide in combination with dexamethasone, PLD, and bortezomib (DVD-R) showed that both efficacy and tolerability may be improved by changing the doses and schedules of these drugs (Berenson et al, 2012). These results imply that the combination of POM, DEX and PLD may be an effective regimen for treating R/R MM pts. We conducted a phase 1/2 trial investigating the safety and efficacy of POM in combination with IV DEX and PLD using our modified dose, schedule, and longer 28-day cycle for pts with R/R MM. Methods For enrollment into the phase 1 portion of the study, eligible pts had to show progressive MM at the time of enrollment. For participation in the phase 2 portion, pts had to be refractory to LEN (singe-agent or in combination) demonstrated by progressive disease while receiving this IMiD or relapsed within 8 weeks of their last dose. Pts who received previous POM treatment were ineligible. During the phase 1 part of the trial, POM was administered orally at 2, 3, or 4 mg daily in 3 successive cohorts of 3 pts each on days 1-21 of each 28-day cycle. DEX (40 mg intravenously over 30 min) and PLD (5 mg/m2infused over 30-90 min) both were given on days 1, 4, 8, and 11 of each cycle. POM doses were escalated per cohort until maximum tolerated dose (MTD) was reached. Phase 2 patients were all enrolled at what was established as the MTD. Results As of July 9, 2013, 33 pts were registered: 11 and 22 enrolled in the phase 1 and 2 portions, respectively. Fifteen patients have discontinued treatment thus far and 18 remain active. Pts had received a median of 5 prior treatments (range, 1-18) with a median of 1 prior PLD regimen (range, 0-2) and 1 prior IMiD regimen (range, 0-4). Pts have completed a median of 4 cycles (range: 0-8) with a median of 3.2 months of follow up (range: 0-9.7). During the phase 1 portion, no dose-limiting toxicities were identified, so the highest administered dose of 4 mg was initially established as the MTD. However, neutropenia ≥ G3 was observed in 10/17 phase 2 pts (58.8%) at this dose; and, as a result, the protocol was amended so that the MTD was lowered to 3 mg for all phase 2 pts beyond the 29thpt (n = 4). Thirty-two pts have received study drug. Twenty-nine pts were evaluable for response at data cutoff as 3 were active but had not yet had any post-baseline disease assessments. Of the 29 considered evaluable, overall response rate and clinical benefit rates were 34.5% and 48.3%, respectively, Six pts (20.7%) showed stable disease while 8 (27.6%) pts exhibited progressive disease. There was ≥ grade 3 (G3) neutropenia in 12 (37.5%) pts. Two pts experienced this toxicity during the phase 1 portion (3 mg and 4 mg doses- 1 each) whereas the other 10 pts experienced this side effect at the 4 mg dose during phase 2 enrollment. Following the lowering of the MTD to 3 mg due to this issue, neutropenia (≥ G3) has not been observed to date. Other treatment-emergent AEs ≥ G3 occurring in more than 1 pt were leukopenia in 12 (37.5%), lymphopenia in 8 (25%), anemia in 3 (9.4%), hyponatremia in 3 (9.4%), thrombocytopenia in 2 (6.3%), and duodenal ulcers in 1 (3.4%) pts. One pt died during treatment due to sepsis. Conclusions Results from this phase 1/2 trial demonstrate that the combination of pomalidomide with dexamethasone and PLD using a 28-day cycle shows efficacy for MM pts with progressive disease who are refractory to lenalidomide. Notably, less neutropenia has been observed at the 3 mg dose of pomalidomide, with 4 mg POM dosing associated with a high incidence of ≥ G3 neutropenia when used in this three-drug combination. Disclosures: Berenson: Celgene: Honoraria, Research Funding, Speakers Bureau. Swift:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vescio:Celgene: Speakers Bureau.

Phase-1 Study of ZIO-101: A New Organic Arsenic Active in Acute Myelogenous Leukemia (AML) and Multiple Myeloma (MM).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1966-1966 ◽  
Author(s):  
James R. Berenson ◽  
Ralph Vincent V. Boccia ◽  
Mohamad A. Hussein ◽  
Andrew Belch ◽  
Lawrence Boise ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Animal Models ◽  
Stable Disease ◽  
Phase 1 ◽  
Single Agent ◽  
Myelogenous Leukemia ◽  
Qtc Prolongation ◽  
Hematological Cancers ◽  
Organic Arsenic

Abstract Background: Although arsenic trioxide (As2O3) is active in vitro against diverse hematological cancers, clinical data show activity only in acute progranulocytic leukemia (APL); there is little if any single-agent activity in multiple myeloma and other hematological cancers. This discordance may be because relatively little As2O3 can be given consequent to its substantial toxicity (especially QTc-prolongation) or because the mode of action (MOA) in APL (differentiation) is inoperative in other hematological cancers (or both). ZIO-101 (S-dimethylarsino-glutathione), a new organic arsenic, is active against diverse cancers in vitro and in animal models including AML and MM. Cell-killing by ZIO-101 is mediated by mitochondrial-disruption and apoptosis-induction rather than the differentiation MOA of As2O3. ZIO-101 can be given at doses ≥ 50-fold higher than As2O3 and achieves 5–10-fold higher intracellular concentrations at equimolar extracellular As concentrations. Gene-expression profiling data suggest different cellular responses to ZIO-101 and As2O3. These features make ZIO-101 attractive for evaluation in AML and MM. Methods: 2 phase-1 studies evaluating safety, activity and pharmacokinetic (PK) profile of ZIO-101 in 21 subjects with advanced AML (N=8) or MM (N=13). Median age is 58 y (range, 41–85 y). Median N of prior therapies is 5 (range, 2–12) including 4 subjects failing prior As2O3 therapy. Starting dose was 78 mg/me2/d IV for 5 consecutive d every 4 w. Results: Subjects received a median of 2 cycles (range, 1–6). Therapy was well-tolerated; adverse events ≥ grade-2 occurring in > 25% of subjects included neutropenia, hypokalemia and hyperglycemia. There was no clinically-important renal, liver or heart toxicity nor QTc-prolongation. Maximum tolerated dose (MTD) was 420 mg/me2/d. Pharmacokinetic (PK) studies at this dose showed a tmax=1 h (SD±0.9), Cmax=1.06 μg/mL (SD±0.07 μg/mL), t1/2=17.8 h (SD±1.4 h) and AUC0-∞=25.9 μg·h/mL (SD±0.8 μg·h/mL). 4 subjects with AML had stable disease (SD) after 1 cycle and received 2–4 more cycles before progressing. Blood myeloblasts decreased substantially in 1 subject and completely resolved in 2. Bone marrow myeloblasts decreased in 1. 1 subject with prior myelodysplastic syndrome (MDS) stopped requiring frequent RBC transfusions. 1 subject with rapidly-progressing As2O3- and bortezumib-resistant MM has stable disease (SD) >6 mo. Conclusions: These early data suggest activity of ZIO-101 in advanced AML and MM. The MTD is 420 mg/me2/d, ≥ 50-fold higher than As2O3. Plasma levels exceed the IC50 for AML and MM cell in vitro and animal models. Clinically-important QTc-prolongation was not seen. Some subjects failing As2O3 responded to ZIO-101 indicating efficacy of a higher dose, different MOA or both. Because of these favorable results phase-2 studies in hematological cancers are in progress.

Stew in its Own Juice: Protein Homeostasis Machinery Inhibition Reduces Cell Viability in Multiple Myeloma Cell Lines

2019 ◽  
Vol 19 (2) ◽  
pp. 112-119 ◽  
Author(s):  
Mariana B. de Oliveira ◽  
Luiz F.G. Sanson ◽  
Angela I.P. Eugenio ◽  
Rebecca S.S. Barbosa-Dantas ◽  
Gisele W.B. Colleoni
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Cell Viability ◽  
Cell Lines ◽  
Treatment Options ◽  
Compensatory Mechanism ◽  
Protein Homeostasis ◽  
Protein Response ◽  
Rpmi 8226

Introduction:Multiple myeloma (MM) cells accumulate in the bone marrow and produce enormous quantities of immunoglobulins, causing endoplasmatic reticulum stress and activation of protein handling machinery, such as heat shock protein response, autophagy and unfolded protein response (UPR).Methods:We evaluated cell lines viability after treatment with bortezomib (B) in combination with HSP70 (VER-15508) and autophagy (SBI-0206965) or UPR (STF- 083010) inhibitors.Results:For RPMI-8226, after 72 hours of treatment with B+VER+STF or B+VER+SBI, we observed 15% of viable cells, but treatment with B alone was better (90% of cell death). For U266, treatment with B+VER+STF or with B+VER+SBI for 72 hours resulted in 20% of cell viability and both treatments were better than treatment with B alone (40% of cell death). After both triplet combinations, RPMI-8226 and U266 presented the overexpression of XBP-1 UPR protein, suggesting that it is acting as a compensatory mechanism, in an attempt of the cell to handle the otherwise lethal large amount of immunoglobulin overload.Conclusion:Our in vitro results provide additional evidence that combinations of protein homeostasis inhibitors might be explored as treatment options for MM.

scholarly journals Pharmacodynamic, pharmacokinetic, and phase 1a study of bisthianostat, a novel histone deacetylase inhibitor, for the treatment of relapsed or refractory multiple myeloma

2021 ◽  
Author(s):  
Yu-bo Zhou ◽  
Yang-ming Zhang ◽  
Hong-hui Huang ◽  
Li-jing Shen ◽  
Xiao-feng Han ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Targets ◽  
Single Agent ◽  
Hdac Inhibitors ◽  
Preclinical Study ◽  
Parp Cleavage ◽  
Rpmi 8226 ◽  
Ongoing Phase

AbstractHDAC inhibitors (HDACis) have been intensively studied for their roles and potential as drug targets in T-cell lymphomas and other hematologic malignancies. Bisthianostat is a novel bisthiazole-based pan-HDACi evolved from natural HDACi largazole. Here, we report the preclinical study of bisthianostat alone and in combination with bortezomib in the treatment of multiple myeloma (MM), as well as preliminary first-in-human findings from an ongoing phase 1a study. Bisthianostat dose dependently induced acetylation of tubulin and H3 and increased PARP cleavage and apoptosis in RPMI-8226 cells. In RPMI-8226 and MM.1S cell xenograft mouse models, oral administration of bisthianostat (50, 75, 100 mg·kg-1·d-1, bid) for 18 days dose dependently inhibited tumor growth. Furthermore, bisthianostat in combination with bortezomib displayed synergistic antitumor effect against RPMI-8226 and MM.1S cell in vitro and in vivo. Preclinical pharmacokinetic study showed bisthianostat was quickly absorbed with moderate oral bioavailability (F% = 16.9%–35.5%). Bisthianostat tended to distribute in blood with Vss value of 0.31 L/kg. This distribution parameter might be beneficial to treat hematologic neoplasms such as MM with few side effects. In an ongoing phase 1a study, bisthianostat treatment was well tolerated and no grade 3/4 nonhematological adverse events (AEs) had occurred together with good pharmacokinetics profiles in eight patients with relapsed or refractory MM (R/R MM). The overall single-agent efficacy was modest, stable disease (SD) was identified in four (50%) patients at the end of first dosing cycle (day 28). These preliminary in-patient results suggest that bisthianostat is a promising HDACi drug with a comparable safety window in R/R MM, supporting for its further phase 1b clinical trial in combination with traditional MM therapies.

scholarly journals Loss of Phosphatase and Tensin Homolog or Phosphoinositol-3 Kinase Activation and Response to Trastuzumab or Lapatinib in Human Epidermal Growth Factor Receptor 2–Overexpressing Locally Advanced Breast Cancers

2011 ◽  
Vol 29 (2) ◽  
pp. 166-173 ◽  
Author(s):  
Bhuvanesh Dave ◽  
Ilenia Migliaccio ◽  
M. Carolina Gutierrez ◽  
Meng-Fen Wu ◽  
Gary C. Chamness ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Breast Cancers ◽  
Trastuzumab Resistance ◽  
Epidermal Growth

Purpose Phosphatase and tensin homolog (PTEN) loss or activating mutations of phosphoinositol-3 (PI3) kinase (PIK3CA) may be associated with trastuzumab resistance. Trastuzumab, the humanized human epidermal growth factor receptor 2 (HER2) monoclonal antibody, and lapatinib, an epidermal growth factor receptor/HER2 tyrosine kinase inhibitor, are both established treatments for HER2-overexpressing breast cancers. Understanding of the cellular response to HER2-targeted therapies is needed to tailor treatments and to identify patients less likely to benefit. Methods We evaluated the effect of trastuzumab or lapatinib in three HER2-overexpressing cell lines. We confirmed the in vitro observations in two neoadjuvant clinical trials in patients with HER2 overexpression; 35 patients received trastuzumab as a single agent for the first 3 weeks, then docetaxel every 3 weeks for 12 weeks (trastuzumab regimen), whereas 49 patients received lapatinib as a single agent for 6 weeks, followed by trastuzumab/docetaxel for 12 weeks before primary surgery (lapatinib regimen). Apoptosis, Ki67, p-MAPK, p-AKT, and PTEN were assessed by immunohistochemistry. Genomic DNA was sequenced for PIK3CA mutations. Results Under low PTEN conditions, in vitro data indicate that lapatinib alone and in combination with trastuzumab was effective in decreasing p-MAPK and p-AKT levels, whereas trastuzumab was ineffective. In the clinical trials, we confirmed that low PTEN or activating mutation in PIK3CA conferred resistance to the trastuzumab regimen (P = .015), whereas low PTEN tumors were associated with a high pathologic complete response rate (P = .007). Conclusion Activation of PI3 kinase pathway is associated with trastuzumab resistance, whereas low PTEN predicted for response to lapatinib. These observations support clinical trials with the combination of both agents.

scholarly journals Efficacy and Safety of Daratumumab Combined With All-Trans Retinoic Acid in Relapsed/Refractory Multiple Myeloma

2021 ◽  
Author(s):  
Kristine A. Frerichs ◽  
Monique Christina Minnema ◽  
Mark-David Levin ◽  
Annemiek Broijl ◽  
Gerard MJ Bos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stable Disease ◽  
Immune Cell ◽  
Ex Vivo ◽  
Phase 1 ◽  
Single Agent ◽  
Flow Cytometric Analysis ◽  
Optimal Dose ◽  
Efficacy And Safety ◽  
Cd38 Expression

The efficacy of daratumumab is partially dependent on CD38 expression on multiple myeloma (MM) cells. We have previously shown that ATRA upregulates CD38 expression and reverts daratumumab-resistance ex vivo. We therefore evaluated the optimal dose, efficacy and safety of daratumumab combined with ATRA in daratumumab-refractory MM patients in a phase 1/2 study (NCT02751255). In part A of the study, 63 patients were treated with daratumumab monotherapy. Fifty daratumumab-refractory patients were subsequently enrolled in part B, and treated with daratumumab (re-intensified schedule) combined with ATRA until disease progression. The recommended phase 2 dose of ATRA in combination with daratumumab was defined as 45 mg/m2. At this dose, the overall response rate (ORR) was 5%, indicating that the primary endpoint (ORR≥15%) was not met. However, the majority of patients (66%) achieved at least stable disease. After a median follow-up of 43 months, the median PFS for all patients was 2.8 months. Patients who previously achieved at least a partial response or minimal response/stable disease with prior daratumumab monotherapy had a significantly longer PFS, compared to those who immediately progressed during daratumumab as single agent (median PFS 3.4 and 2.8 versus 1.3 months). The median OS was 19.1 months. The addition of ATRA did not increase the incidence of adverse events. Flow cytometric analysis revealed that ATRA temporarily increased CD38 expression on immune cell subsets. In conclusion, the addition of ATRA and re-intensification of daratumumab had limited activity in daratumumab-refractory patients, which may be explained by the transient upregulation of CD38 expression.

The treatment of advanced stage favorable histology non-Hodgkin's lymphoma: a preliminary report of a randomized trial comparing single agent chemotherapy, combination chemotherapy, and whole body irradiation

Blood ◽  
1981 ◽  
Vol 58 (3) ◽  
pp. 592-598 ◽  
Author(s):  
RT Hoppe ◽  
P Kushlan ◽  
HS Kaplan ◽  
SA Rosenberg ◽  
BW Brown
Keyword(s):  
Clinical Trials ◽  
Combination Chemotherapy ◽  
Treatment Options ◽  
Single Agent ◽  
Treatment Protocol ◽  
Whole Body ◽  
Remission Induction ◽  
Advanced Stage ◽  
Favorable Histology ◽  
Hodgkin's Lymphomas

Abstract Between 1975 and 1978, 51 patients with favorable histology non- Hodgkin's lymphomas, pathologic stage III-IV, were treated prospectively on a randomized treatment protocol. Treatment options were single alkylating agent chemotherapy, combination chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP), or fractionated whole body irradiation followed by low dose involved field irradiation. The median follow-up interval in this group of patients is not 41 mo. Actuarial survival is excellent, 84% at 4 yr for the entire group, with similar survival observed for each of the three treatment options. Initial complete remission rates (64%, 88%, and 71%) were not significantly different in the three treatment arms. Frequent relapse after initial remission induction was noted, however, with a freedom from relapse at 4 yr of only 25%. The toxicities of the three therapies were acceptable. Acute complications of therapy were most numerous in the group of patients treated with CVP; however, long-term hematologic depression was most commonly observed in patients treated with whole body irradiation. In general, hematologic complications were more frequent among patients who had marrow involvement and intact spleens at the time of initial therapy. The relationship of this study to other clinical trials in the management of patients with advanced stage favorable histology lymphomas and its implications for future clinical trials are discussed.

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