Phase 1 Study of Bisthianostat, an Orally Efficacious Pan-HDAC Inhibitor: Part Results of Safety, Pharmacokinetics and Efficacy in Patients with Relapsed or Refractory Multiple Myeloma

Background: Multiple myeloma (MM) is the second most common hematological malignancy. This disease remains incurable as nearly all patients will relapse and become refractory to established MM therapy. Thus, new treatment option for relapsed or refractory (R/R) MM is needed, particularly those with different mechanisms of action. One such approach is to inhibit histone deacetylase (HDAC) and produce synergistic anti-myeloma activity via mechanisms of epigenetic modulations. In 2015, panobinostat was approved by US FDA as the first HDACi to treat R/R MM in combination with bortezomib and dexamethasone. Bisthianostat is a novel bisthiazole-based HDACi evolved from the thiazole-thiazoline cap group in natural product Largazole (Nan et al., ACS Med Chem Lett. 2014). It is orally available and displayed inhibition against a series of MM cell lines. Here we presented preliminary in-human findings from CH-020PI study, an ongoing phase 1 study of bisthianostat. (Trial registered at ClinicalTrial.gov: NCT03618602) Methods: CH-020PI is a first-in-human study to investigate the safety, tolerability, pharmacokinetics, and efficacy of bisthianostat in R/R MM patients. It is a single center, open-label, single arm, dose escalating phase I study. A standard 3+3 cohort design with 100mg as the starting dose was used to determine the maximum tolerated dose of bisthianostat. This study comprised two phases: a pharmacokinetics phase and an expansion phase. In the pharmacokinetics phase, a single-dose of bisthianostat was administered on day 1, and then multiple-dose was administered on a twice-weekly schedule for 4 consecutive weeks. Patients in the expansion phase received continuous bisthianostat twice weekly until progressive disease or unacceptable toxicities. Results: Until 30 June 2019, 8 patients were enrolled at 3 dose levels from 100 to 400mg. The median age at enrollment was 62 years (range, 51-70 years). The median number of previous lines of therapy was 5 (range, 2-6). Per protocol, all of 8 patients were evaluable for pharmacokinetics, toxicities and efficacy. In the pharmacokinetic evaluation, for all the 8 patients tested at day 1, the peak concentration of bisthianostat was reached within 2.3 hours; half life time were around 4 hours; bisthianostat uptake represented by AUClast were in good proportion to the level of dose as 100, 200 and 400mg, respectively. Similar results were observed at day 28. Any grade hematological treatment-related adverse events (AEs) occurred in 4 of 8 patients (50%), while grade 3/4 hematological AEs occurred in 2 (25%) patients. Any grade non-hematological treatment-emergent AEs were observed in 3 (37.5%) patients; no grade 3/4 non-hematological AEs were reported. No patient discontinued the treatment of bisthianostat due to AEs. Except patient 007 (200mg cohort) experienced a grade 2 nausea, no patients experienced diarrhea, nausea, or vomiting. It is worthy to note that gastrointestinal toxicity is common with the use of panobinostat, a FDA-approved HDAC inhibitor. Overall single-agent efficacy was modest, and stable disease (SD) was observed in 4 (50%) patients. At the time of data cut-off for statistical analysis, no dose-limiting toxicity has been observed. Conclusions: Bisthianostat proved to be well absorbed and tolerated. It exhibited modest anti-tumor efficacy in our cohort of heavily pretreated patients with R/R MM. This phase I clinical trial is currently ongoing, and future trials should compare different doses and schedules of the combination in order to optimize the treatment tolerability and enhance its efficacy. Disclosures No relevant conflicts of interest to declare.

Download Full-text

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

Blood ◽

10.1182/blood.v124.21.4774.4774 ◽

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.

Download Full-text

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

Blood ◽

10.1182/blood.v106.11.2555.2555 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2555-2555 ◽

Cited By ~ 8

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.

Download Full-text

Results of a Phase I Trial of SGN-40 (Anti-huCD40 mAb) in Patients with Relapsed Multiple Myeloma.

Blood ◽

10.1182/blood.v108.11.3576.3576 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3576-3576 ◽

Cited By ~ 9

Author(s):

Mohamad A. Hussein ◽

James R. Berenson ◽

Ruben Niesvizky ◽

Nikhil C. Munshi ◽

Jeffrey Matous ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Aseptic Meningitis ◽

Dose Escalation ◽

Single Agent ◽

Objective Response ◽

Lymphocytic Leukemia ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Grade 3

Abstract SGN-40 is a humanized anti-CD40 monoclonal antibody that has demonstrated potent in vitro and in vivo efficacy against cell lines expressing CD40, a member of the tumor necrosis factor receptor family. CD40 is widely expressed on tumors of B-cell origin, including myeloma, non-Hodgkin’s lymphoma, Hodgkin’s disease, and chronic lymphocytic leukemia. SGN-40 has been evaluated in a phase I, multi-dose, single-agent, dose escalation study for patients with relapsed or refractory multiple myeloma. This single-arm trial was designed to evaluate safety, pharmacokinetics, immunogenicity, and antitumor activity. Thirty-two patients were treated at five clinical sites. Patients had been heavily pretreated with a median of four prior regimens and 4.8 years since diagnosis. Initially, patients were treated with four weekly infusions at a cohort-specific dose. This schedule was well-tolerated at 0.5, 1.0 and 2.0 mg/kg/wk; however, two of three patients experienced dose-limiting toxicities following the first dose at 4 mg/kg. One patient had aseptic meningitis (grade 3) and another had headache (grade 3) and aseptic meningitis (grade 4); both patients fully recovered after several days of symptom management. Subsequently, the protocol was amended to allow intra-patient dose-loading, which resulted in successful dose escalation to 8 mg/kg, the highest dose tested. There was neither recurrence of grade 3 neurotoxicity nor evidence of cumulative toxicity. Drug-related adverse events were mostly grade 1 or 2 and included: fatigue (38%), headache (34%), nausea (16%), conjunctivitis (13%), diarrhea (13%), vomiting (13%), anemia (9%), anorexia (9%), chills (9%), and pyrexia (9%). Transient grade 3 elevation of hepatic transaminases (1) and grade 3 neutropenia (1) were observed. Overall, toxicity did not appear to increase in incidence or severity at higher doses. Patients were evaluated at baseline and end of treatment for development of anti-SGN-40 antibodies. Of 30 patients for whom appropriate samples were available for testing, only one low-titer immune response (16 ng/mL) was detected, suggesting that immunogenicity does not appear to be a significant problem in this patient population. Pharmacokinetic analysis demonstrates dose-proportional changes in Cmax and AUC with a relatively short terminal half-life, similar to that seen in non-human primates. Final analysis of SGN-40 serum levels is ongoing. Although several patients demonstrated decreased M-protein and improvement in subjective symptoms, no patients met criteria for objective response. Five patients (16%) had stable disease at the time of restaging. In summary, dose-dependent toxicity was established only in relation to the first dose of SGN-40, which may be due to partial agonistic signal transduction. Using a dose-loading schedule, SGN-40 was administered up to 8 mg/kg without reaching a maximum tolerated dose. Some patients with advanced myeloma appeared to derive clinical benefit from therapy, and further development of this antibody, either as monotherapy or in combination with other anti-myeloma therapies, is indicated.

Download Full-text

ARRY-520 Shows Durable Responses in Patients with Relapsed/Refractory Multiple Myeloma in a Phase 1 Dose-Escalation Study

Blood ◽

10.1182/blood.v118.21.1860.1860 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1860-1860 ◽

Cited By ~ 5

Author(s):

Jatin J Shah ◽

Jeffrey Zonder ◽

Adam Cohen ◽

Robert Z. Orlowski ◽

Raymond Alexanian ◽

...

Keyword(s):

Multiple Myeloma ◽

Febrile Neutropenia ◽

Dose Escalation ◽

Safety Profile ◽

Research Funding ◽

Phase 1 ◽

Phase 1 Study ◽

Acceptable Safety Profile ◽

Heavily Pretreated ◽

Grade 3

Abstract Abstract 1860 Background: ARRY-520 is a potent, selective inhibitor of kinesin spindle protein (KSP, eg5) which is required for cell cycle progression through mitosis. Treatment with ARRY-520 arrests cells in mitosis with subsequent induction of apoptosis due to degradation of survival signals during mitotic arrest. Cancers, such as multiple myeloma (MM), that depend on the short-lived survival protein Myeloid cell leukemia (MCL)-1 are highly sensitive to treatment with ARRY-520 in preclinical MM models, providing a strong rationale for its clinical investigation in this disease. Methods: This Phase 1 study was designed to evaluate the safety, pharmacokinetics (PK), preliminary efficacy and biological activity of ARRY-520 administered intravenously on Days 1 and 2 every 2 weeks without/with granulocyte colony-stimulating factor (G-CSF) support. Eligible patients (pts) had relapsed or refractory MM with ≥ 2 prior lines of therapy (including both bortezomib [BTZ] and an immunomodulatory [IMiD] agent), unless refusing or ineligible for this therapy. Cohorts were enrolled in a classical 3+3 dose escalation design. Results: Enrollment in this Phase 1 study is complete. Thirty-one pts have been treated, with a median age of 60 years (range 43–79) and a median of 6 prior regimens (range 2–16). All pts received a prior proteasome inhibitor (30 pts BTZ, 4 pts carfilzomib) and an IMiD-based agent (28 pts lenalidomide, 23 pts thalidomide). Twenty-four pts had an autologous stem cell transplant. The maximum tolerated dose (MTD) was determined to be 1.25 mg/m2/day without G-CSF. As neutropenia was the dose-limiting toxicity (DLT), dose escalation with G-CSF support was conducted and the MTD for ARRY-520 with G-CSF was determined to be 1.5 mg/m2/day. At the MTD, 1 of 7 pts had a DLT of febrile neutropenia. At doses above the MTD, additional DLTs of Grade 3 mucositis and Grade 3 corneal disorder were observed. ARRY-520 demonstrated an acceptable safety profile. The most commonly reported treatment-related adverse events (AEs) included hematologic events (anemia, leukopenia, neutropenia, thrombocytopenia), as well as anorexia, blurred vision, diarrhea, dizziness, fatigue, febrile neutropenia, mucositis, nausea and rash. No treatment-related AEs of neuropathy or alopecia were reported at the MTD. ARRY-520 has been dosed over extended periods of time (to date, median 7 cycles [range 1–44]), with no evidence of cumulative toxicity. The plasma concentrations of ARRY-520 were determined over a 7-day period during Cycle 1 following the Day 1 and 2 infusions of ARRY-520. The preliminary noncompartmental PK parameter estimates in this population were similar to those observed in prior oncology studies. The PK was characterized by low clearance (CL = 2.2 L/hr/m2) and a large volume of distribution (Vss = 232 L/m2). The t1/2 of elimination was very long (67 hrs). Concentrations were typically maintained above the in vitro IC50 for KSP inhibition for ≥ 7 days suggesting therapeutically active concentrations of drug were maintained in pts for sustained periods. Further analyses of PK relative to safety and activity are on-going. ARRY-520 showed activity as a single agent across a range of doses in this heavily pretreated population (31 evaluable pts) with 3 confirmed partial responses (PR) and 1 confirmed minimal response (MR) per International Melanoma Working Group (IMWG) and European Group for Blood and Marrow Transplantation (EMBT) criteria. PRs had a median of 7 prior therapies (range 2–8). Responses were durable; to date, the durations of responses for PRs were 3.4+ months (mos), 11.9+ mos and 12.0 mos, respectively. Of interest, the time to response with ARRY-520 was prolonged, with a median time to PR of 3.7 mos (range 3.7–8.1). Notably, responses were observed in pts refractory to multiple standard-of-care agents. In addition, 4 pts experienced a best response of stable disease (SD) lasting ≥ 10 mos. To date, 5 pts remain on study, including 2 of 3 PRs. Conclusions: In this Phase 1 study, ARRY-520 shows promising evidence of clinical activity, with a long duration of response and an acceptable safety profile in heavily pretreated MM Patients. A Phase 2 portion of the study is ongoing to obtain additional information on the efficacy, safety and biological effects of ARRY-520 at 1.5 mg/m2/day with G-CSF support. Disclosures: Shah: Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy; Onyx: Consultancy, Research Funding. Off Label Use: ARRY-520. Zonder:Millenium: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Medtronics: Honoraria; Amgen: Consultancy. Cohen:Celgene: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Orlowski:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Alexanian:Array BioPharma: Research Funding. Thomas:Array BioPharma: Research Funding; Centecor: Research Funding; Novartis: Research Funding; Immunomedics: Research Funding; Celgene: Research Funding; Millenium: Research Funding. Weber:Array BioPharma: Research Funding. Kaufman:Keryx: Consultancy; Celgene: Research Funding; Merck: Research Funding. Walker:Array BioPharma: Employment, Equity Ownership. Litwiler:Array BioPharma: Employment. Karan:Array BioPharma: Employment. Hilder:a: Employment. Ptaszynski:Array BioPharma Inc.: Consultancy. Lonial:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy.

Download Full-text

Phase 1 Study of the Investigational Proteasome Inhibitor Ixazomib Alone or in Combination with Lenalidomide–Dexamethasone (Rd) in Japanese Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM)

Blood ◽

10.1182/blood.v124.21.5752.5752 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5752-5752 ◽

Cited By ~ 2

Author(s):

Hiroshi Handa ◽

Kenshi Suzuki ◽

Takaaki Chou ◽

Takafumi Matsushima

Keyword(s):

Multiple Myeloma ◽

Proteasome Inhibitor ◽

Research Funding ◽

Phase 1 ◽

Single Agent ◽

Japanese Patients ◽

M Protein ◽

Phase 3 ◽

Grade 3 ◽

Ongoing Phase

Background Ixazomib is the first oral proteasome inhibitor to be investigated clinically for the treatment of MM. Phase 1 studies have shown single-agent activity and manageable toxicities in RRMM (Kumar et al. Blood 2014) and phase 1/2 studies have suggested the feasibility and activity of weekly oral ixazomib plus Rd in previously untreated MM (Kumar et al. ASH 2012; Richardson et al. ASH 2013). These findings have led to ongoing phase 3 trials of weekly ixazomib 4 mg + Rd in RRMM and previously untreated MM. However, the early-phase studies were conducted in Western pts. This phase 1, open-label multicenter study aimed to determine the safety, tolerability, and pharmacokinetics (PK) of weekly ixazomib alone or with Rd in Japanese pts with RRMM (Japic Clinical Trials Information no. 121822). Methods Primary objectives were to evaluate the safety and tolerability, including dose-limiting toxicities (DLTs) and adverse events (AEs), and the PK of ixazomib alone or with Rd. A secondary objective was evaluation of antitumor activity. Japanese pts aged ≥20 years with RRMM who had received at least 2 prior regimens, which must have included bortezomib, thalidomide or lenalidomide, and corticosteroids, were eligible. All had measurable disease and ECOG performance status of 0–2. Pts with grade ≥2 peripheral neuropathy or grade ≥2 diarrhea at study entry were excluded. Pts received ixazomib 4 mg on days 1, 8, and 15 of 28-day cycles, alone or with Rd (lenalidomide 25 mg on days 1–21, dexamethasone 40 mg on days 1, 8, 15, and 22), per the regimen used in the ongoing phase 3 trials. AEs were graded per NCI-CTCAE v4.03. Blood samples for PK analysis were taken at multiple time points prior to and after dosing on days 1 and 15 of cycle 1. Responses were assessed per IMWG uniform response criteria. Results Fourteen pts were enrolled; 8 (57%) were male, median age was 62.5 yrs (range 53–71), 4 pts were aged ≥65 yrs, median number of prior therapies was 7. Seven pts received single-agent ixazomib and 7 received ixazomib + Rd. One pt in each cohort was excluded from the DLT-evaluable population. Two patients experienced DLTs in cycle 1: 1 pt receiving single-agent ixazomib had grade 4 thrombocytopenia and grade 3 diarrhea, hypertension, hypokalemia, hyponatremia, and nausea; 1 pt in the ixazomib + Rd cohort had grade 4 thrombocytopenia and neutropenia. All events were considered treatment-related. At data cut-off (Jan 6 2014), 6 pts remained on treatment and 8 had discontinued due to: progressive disease (PD; n=3), AEs (n=3), symptomatic deterioration, and protocol violation (each n=1). At data cut-off, pts (n=14) had received a median of 6 cycles of ixazomib (range 1–21); the 7 pts in the ixazomib + Rd cohort had received a median of 4 cycles (range 1–12) of ixazomib + Rd. Thirteen (93%) pts experienced treatment-related AEs; the most common were neutropenia (71%), thrombocytopenia (71%), leukopenia (64%), lymphopenia (57%), and diarrhea (50%). There were no cases of peripheral neuropathy. Nine (64%) pts had grade ≥3 AEs; the most common were lymphopenia (50%), neutropenia (43%), and thrombocytopenia (36%). Two (14%) pts (single-agent cohort) had serious AEs (grade 2 bronchitis in 1 pt, and grade 4 thrombocytopenia and grade 3 hypokalemia in 1 pt). Three pts discontinued due to AEs; 1 due to diarrhea in the single-agent cohort, and 1 due to neutropenia and 1 due to thrombocytopenia in the ixazomib + Rd cohort. There were no deaths. PK data showed ixazomib was rapidly absorbed with a Tmax at 1.08–1.83 hrs. Terminal half-life (geometric mean) was 5.7 days for single-agent ixazomib and 5.2 days for ixazomib + Rd. There were no substantial differences in the ixazomib PK profile between the two cohorts. Thirteen pts were response-evaluable. One pt (ixazomib + Rd cohort) had a partial response; at data cut-off, this pt remained in response with a 100% M-protein reduction (unconfirmed VGPR) and duration of response of ~10.8 months. Seven pts had stable disease (including 3 with M-protein reductions of 25–50%), 2 had PD, and 3 were not assessable. Conclusions These data suggest that ixazomib 4 mg alone or with Rd is feasible and tolerable in Japanese pts with RRMM. The AEs were manageable, reflecting the AE profile seen in Western populations, supporting the use of this dose and schedule in Japanese pts. Disclosures Handa: Celgene: Research Funding; Yakult: Research Funding; Kirin: Research Funding; Chugai: Research Funding. Off Label Use: Investigational agent ixazomib for the treatment of Japanese patients with relapsed and/or refractory multiple myeloma.. Matsushima:Takeda Pharmaceutical Company Limited : Employment.

Download Full-text

Pharmacokinetics and safety of an oral ALK inhibitor, ASP3026, observed in a phase I dose escalation trial.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.2602 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 2602-2602 ◽

Cited By ~ 6

Author(s):

Amita Patnaik ◽

Patricia LoRusso ◽

Howard A. Ball ◽

Erkut Bahceci ◽

Geoffrey Yuen ◽

...

Keyword(s):

Dose Reduction ◽

Dose Escalation ◽

Phase 1 ◽

Single Agent ◽

Clinical Activity ◽

Expansion Phase ◽

Advanced Malignancies ◽

Grade 3 ◽

Ecog Ps ◽

Clinical Trial Information

2602 Background: ASP3026 (3026) is a selective, potent, ATP-competitive, small molecule oral inhibitor of ALK receptor tyrosine kinase that has not previously been tested in humans. A Phase 1 dose-escalation trial, using a 3+3 design, evaluating 3026 as an oral single agent was conducted to investigate PK (Day 1 and Day 28), safety and clinical activity in patients (pts) with advanced malignancies (excluding leukemias) of ECOG PS 2 or less. Methods: 3026 was administered under fasting conditions on a continuous schedule to pts in successive dose-escalating cohorts at doses ranging from 25 mg QD to 800 mg QD. Results: Thirty pts were enrolled into the dose escalation part of the study. The MTD was determined based on DLT data from cycle 1. Three DLTs were observed: grade 2 nausea and vomiting leading to dose reduction at 525 mg QD; grade 3 rash leading to dose reduction, and grade 3 ALT/AST increase leading to study withdrawal at 800 mg QD. The most common AEs were constipation, vomiting, diarrhea, nausea and abdominal pain, and all AEs were manageable and reversible. Median AUC and Cmax increased proportionally with dose from 25 mg QD to 800 mg QD. There was no evidence of non-linear PK at ASP3026 doses >25 mg QD. The median terminal half-life was approximately 10 - 41 hours. Overall, A3026 appears well absorbed with median Tmax around 3 hours for both Day 1 and Day 28. Terminal T1/2 appears adequate for one daily dosing with median values ranging from approximately 18 to 34 hours. Based on visual inspection of pre-dose (trough) values from Days 8, 15, 22, and 28 it appears that steady-state conditions are achieved by day 28. Conclusions: The MTD of 3026 is 525 mg QD. Treatment with 3026 resulted in a promising safety and PK profile in pts with advanced malignancies. Further evaluation of 3026 in pts with tumors harboring gene mutation or ALK fusion genes in the cohort expansion phase at the MTD is ongoing. Clinical trial information: NCT01401504.

Download Full-text

A Phase 1 Study of Intravenous Busulfan as a Conditioning Regimen for Multiple Myeloma

Cell Transplantation ◽

10.1177/0963689719880541 ◽

2019 ◽

Vol 28 (12) ◽

pp. 1624-1631

Author(s):

Sabarinath V. Radhakrishnan ◽

Michael Boyer ◽

Catherine M. Sherwin ◽

Maurizio Zangari ◽

Guido Tricot

Keyword(s):

Multiple Myeloma ◽

Elderly Patients ◽

Phase 1 ◽

Single Agent ◽

Conditioning Regimen ◽

Primary Objective ◽

Pharmacokinetic Analysis ◽

Dose Escalation Study ◽

Post Transplant ◽

Grade 3

The efficacy of melphalan (MEL) 140 mg/m2 pre-transplant conditioning versus MEL 200 mg/m2 for the elderly is still debated. We hypothesized that single-agent intravenous busulfan (BU) would show significant anti-myeloma efficacy and be better tolerated by elderly patients. A prospective 3+3 dose escalation study enrolled symptomatic multiple myeloma (MM) patients 65 years or older with SWOG performance 0–2 for treatment with intravenous BU pre-transplant at different administration levels. The primary objective was to determine the maximum tolerated dose (MTD) of BU that could be safely given over the least number of days. All patients, except one, received maintenance treatment post-transplant, mostly for 2 years. We enrolled 13 patients, mean age of 73 years (range 68–80). Pharmacokinetic analysis showed no greater than 2% accumulation in the 13 patients, confirming a lack of accumulation in the multi-dose regimen. No deaths occurred in the peri-transplant period. Grade 3/4 adverse effects were hematological, no dose-limiting toxicity was observed and MTD was not reached. Three patients developed grade 3 mucositis but none developed veno-occlusive disease. Ten (77%) patients achieved a complete remission (CR) post-transplant with a remarkably long average time to best response of 6.7 months (range: 6–14 m), and two attained a partial response. Median overall survival was 84 months (95% CI, 21–104) and the median progression-free survival was 60 months (95% CI, 9–93). Our results suggest that IV BU could be an alternative conditioning regimen to MEL 140 in elderly patients with MM, and supports future randomized trials.

Download Full-text

Safety and tolerability of oxaliplatin based pressurized intraperitoneal aerosol chemotherapy (PIPAC) for patients with peritoneal carcinomatosis: A phase I dose-finding study in Asian patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.360 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 360-360 ◽

Cited By ~ 1

Author(s):

Raghav Sundar ◽

Guo Wei Kim ◽

Hon Lyn Tan ◽

Lingzhi Wang ◽

Koy Min Chue ◽

...

Keyword(s):

Peritoneal Carcinomatosis ◽

Dose Escalation ◽

Intraperitoneal Chemotherapy ◽

Phase 1 ◽

Single Agent ◽

Phase 1 Study ◽

Dose Cohort ◽

Asian Patients ◽

Delivery Technique ◽

Grade 3

360 Background: PIPAC is a novel, laparoscopic intraperitoneal chemotherapy delivery technique which aims to improve on hyperthermic intraperitoneal chemotherapy (HIPEC), ameliorating drug distribution and tissue penetration. Thus far, PIPAC has been conducted with oxaliplatin chemotherapy in Europe, at an arbitrary dose of 92mg/m2; 150mg/m2 was found to be intolerable. We conducted a dose-escalation phase 1 study to establish the safety, tolerability and recommended phase 2 dose (RP2D) for PIPAC in Asian patients. Methods: This phase 1 study of oxaliplatin administered via PIPAC was designed as a traditional 3+3 dose escalation study for patients with predominant peritoneal metastasis from a gastrointestinal primary tumor, after failure of standard therapies. Dose levels were planned at 45, 60, 90 and 120mg/m2. Repeat doses of PIPAC were permitted, 6 weeks apart. Dose limiting toxicities (DLT) were defined as any clinically relevant grade 3 adverse events occurring within 28 days after PIPAC. Results: This study included 16 patients (25 PIPAC procedures; 8 gastric, 4 colorectal and 1 gallbladder, pancreas and appendix cancer each). Median age was 62 years, with a median peritoneal carcinomatosis index (PCI) score of 17 (range 1 - 39). Two patients developed pancreatitis (grade 2 and 3) on day 6 and day 9 after PIPAC administration at the dose cohort of 45mg/m2, necessitating cohort expansion to 6 patients. One patient was noted to have asymptomatic grade 3 hyperamylasemia (90mg/m2 cohort). There were no other DLTs and all 3 patients in the highest dose cohort (120mg/m2) tolerated PIPAC well. Nine patients who underwent a 2nd PIPAC procedure had a decrease in PCI score from 18.4 to 15.5; one patient at 120mg/m2 had an improvement in PCI from 30 to 12. Conclusions: The RP2D of PIPAC with oxaliplatin is 120mg/m2. Single agent PIPAC is well tolerated, and future studies with PIPAC must consider a bi-directional approach with the incorporation of systemic therapy, with either chemotherapy or immunotherapy to improve efficacy. Clinical trial information: NCT03172416.

Download Full-text

Phase I Clinical Trial of Oral Administration of the Histone Deacetylase (HDAC) Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) in Patients with Relapsed/Refractory Multiple Myeloma (MM).

Blood ◽

10.1182/blood.v104.11.1503.1503 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1503-1503 ◽

Cited By ~ 8

Author(s):

Paul Richardson ◽

Robert L. Schlossman ◽

Constantine S. Mitsiades ◽

Nikhil C. Munshi ◽

Kathleen Colson ◽

...

Keyword(s):

Clinical Trial ◽

Multiple Myeloma ◽

Phase I ◽

Dose Level ◽

Hdac Inhibitor ◽

Hydroxamic Acid ◽

Phase I Clinical Trial ◽

Hematologic Toxicity ◽

Suberoylanilide Hydroxamic Acid ◽

Grade 3

Abstract Introduction: Histone deacetylases (HDACs) affect cell growth at the transcriptional level by regulating the acetylation status of nucleosomal histones, and HDAC inhibition induces differentiation and/or apoptosis in transformed cells. We have recently shown that HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA), induce apoptosis of human multiple myeloma (MM) cells via a constellation of antiproliferative and/or proapoptotic molecular events, including decreased expression of multiple signaling molecules and oncogenes implicated in MM pathophysiology. Based on these promising pre-clinical data, we embarked on a phase I clinical trial of oral SAHA in patients with advanced MM. Methods: An open-label phase I dose-escalation of oral SAHA (200, 250 and 300 mg po bid for 5 consecutive days followed by 2 days of rest) was administered in 4-week cycles in pts with relapsed/refractory MM. The primary objective was to determine the maximum tolerated dose (MTD), and secondary objectives included evaluation of tumor response, as well as assessment of markers of biologic activity in peripheral blood mononuclear cells and bone marrow plasma cells. Dose limiting toxicity (DLT) was defined as grade 4 or greater hematologic toxicity and/or grade 3 or greater non-hematologic toxicity within the first 28 days of treatment. Results: To date, 8 pts with advanced MM (5 relapsed and 3 with relapsed, refractory MM) have been enrolled at the first 2 dose levels, receiving a median of 3 cycles (range 2–9) of therapy. In 7 evaluable pts, one pt at the 2nd dose level (250 mg po bid) developed DLT with grade 3 fatigue, prompting dose reduction with the next cycle. Other side effects have included grade 2 fatigue (3 pts), grade 2 diarrhea (2 pts), grade 2 indigestion (2 pts) and grade 2 dehydration (2 pts), which have been manageable with appropriate supportive care. In one patient, during cycle 4 at dose level 2, grade 3 dehydration occurred with associated metabolic abnormalities that readily resolved with electrolyte supplementation and rehydration. The patient has continued on therapy at reduced dose (250 mg po bid, 4 days on, 3 days off) without recurrence of this toxicity. Importantly, no significant myelosuppression, neuropathy or sedation, which are associated with other anti-MM agents, has been seen. In 7 evaluable pts: minor responses (MR) were documented in 2 patients (25–50% reduction in serum paraprotein levels); stable disease (SD: less than 25% reduction in paraprotein levels) was observed in 2 pts; and progressive disease (PD) was documented in 3 pts. Conclusion: SAHA is an orally administered HDAC inhibitor with manageable toxicity and preliminary evidence of antitumor activity in advanced MM. Clinical evaluation of this agent continues, with enrolment at 250 mg b.i.d. ongoing, to further define the safety and tolerability at this dose level and provide insight into the future uses of SAHA, either alone or in combination with other agents, to treat pts with advanced MM.

Download Full-text

Voreloxin (formerly known as SNS-595) in Combination with Cytarabine Demonstrates Preliminary Clinical Responses in a Phase 1 Study in Relapsed/Refractory Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v112.11.1955.1955 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1955-1955 ◽

Cited By ~ 1

Author(s):

Jeffrey Lancet ◽

Judith E. Karp ◽

Larry D. Cripe ◽

Gail J. Roboz ◽

Matt Suster ◽

...

Keyword(s):

Ex Vivo ◽

Phase 1 ◽

Single Agent ◽

Clinical Activity ◽

Phase 1 Study ◽

Patient Response ◽

Clinical Responses ◽

Phase 1B ◽

Grade 3 ◽

Refractory Aml

Abstract Background: Voreloxin (formerly SNS-595) is a first-in-class replication-dependent DNA damaging agent that causes apoptosis by DNA intercalation and inhibition of topoisomerase II. A previous phase 1 study of single-agent voreloxin demonstrated acceptable safety and strong signs of clinical activity in patients with relapsed/refractory hematologic malignancies (ASH 2007), where MTD was found to be 72 mg/m2 weekly x 3 and 40 mg/m2 twice weekly x 4. In nonclinical models, the combination of voreloxin and cytarabine demonstrated enhanced activity. Preliminary results of an ongoing phase 1b study of combination voreloxin plus cytarabine in relapsed/refractory AML patients are reported. Objectives: establish safety, tolerability and MTD of escalating doses of voreloxin combination with continuous infusion cytarabine, characterize voreloxin PK in the setting of cytarabine given as a continuous intravenous infusion (CIV) assess clinical activity explore markers of patient response evaluate ex vivo voreloxin sensitivity in bone marrow as a predictor of response. Methods: Open label, doseescalation phase 1b study with a starting dose of voreloxin of 10 mg/m2 (given on days 1,4) in combination with 400 mg/m2/day CIV cytarabine for five days. Dose-limiting toxicities (DLTs) were assessed during cycle 1. PK analyses for voreloxin were performed during cycle 1. Pre- and post-dose PBMC were obtained to evaluate modulation of DNA damage response markers as correlates of patient response. Ex vivo sensitivity to voreloxin of baseline bone marrow samples was evaluated using the CellTiter-Glo® proliferation assay. Clinical response was determined based on IWG criteria. Patients could receive up to 2 courses of induction, and patients achieving CR or CRp could receive up to 2 courses as consolidation. At MTD, an additional cohort of patients will be enrolled to further assess safety. Results: To date, 26 patients have been enrolled and 24 have received treatment. Demographics: 16 males, 8 females, median age 61.4 years (range 30 – 74.5 yrs). Disease status: 17 of 24 treated patients had relapsed disease. Median number of prior therapies was 2 (Range 0–4). Two patients had prior allogeneic stem cell transplant. Dose escalation has proceeded to 80 mg/m2/dose (cohort 6). Safety: a single DLT has been observed (grade 5 septic shock in one patient treated at 70 mg/m2). Grade 3+ related non hematologic AEs ≥ 5% incidence: infections (23%). Grade 3+ hematologic toxicities have been consistent with past experience and include febrile neutropenia, anemia, and thrombocytopenia. The most common reason for early study termination was disease progression. Voreloxin pharmacokinetics were unaffected by cytarabine compared with the single agent phase 1 study. Preliminary clinical responses are listed below in Table 1. Conclusion: Voreloxin given in combination with continuous infusion cytarabine is generally well-tolerated, with encouraging signs of activity in patients with relapsed/refractory AML. Dose escalation continues. Table 1: Clinical Responses by Cohort Cohort Voreloxin Dose Treated/Enrolled DLTs Responses 1 10 4/4 0 0 2 20 3/4 0 1 CR 3 34 4/4 0 2 CR 4 50 6/6 0 2 CR 5 70 7/8 1 2 CR

Download Full-text