A Phase II Study of Oral Panobinostat (LBH589) in Adult Patients with Advanced Refractory Multiple Myeloma

Abstract Panobinostat (LBH589) is a highly potent pan-deacetylase inhibitor (DACi), which induces cytotoxicity at <10nM in multiple myeloma (MM) cell lines resistant to conventional therapies. It modulates 2 targets implicated in MM by controlling cell proliferation and survival through HSP90 and inducing apoptosis through the aggresome pathway. Here we report the preliminary results of a Phase II, single arm, multicenter study of panobinostat in patients with measurable MM disease who had received at least 2 prior lines of therapy (including bortezomib and lenalidomide or thalidomide) and who were also refractory to their most recent line of therapy. The study was designed to assess: response rate (CR/PR) by the IBMTR/EBMTR criteria, safety, and tolerability of 20 mg/day of oral panobinostat given on a Monday/Wednesday/Friday (MWF) dosing schedule. 3 or more responders in 25 patients in stage 1 of the study were required for the initiation of Stage 2. A total of 38 pts (24 males, 14 females; median age 61 years [43–72]) have been enrolled between February and October 2007. Median time since last prior therapy was 33 days, median number of prior therapies was 5 (2–12). Median treatment duration was 45 days (5–377 days). Overall, panobinostat was well tolerated, and no new safety signals were reported. Mild or moderate level of nausea, as well as fatigue/asthenia, occurred in half of the patients. The most common Grade 3/4 AEs were cytopenias, with neutropenia, thrombocytopenia, and anemia in 32%, 26%, and 16% of patients, respectively. Other Grade 3/4 AEs included infections: 8 occurrences (3 of pneumonia; 2 of septic shock; and back pain, hypercalcemia, and hypokalemia in 3 pts each). No cardiac (including significant QTc prolongation, pericarditis, or pericardial effusion) or thromboembolic events were reported. SAEs potentially related to study drug were observed in 3 pts and included nausea (2), diarrhea and vomiting (1), and reduced general condition (1). 5 patients discontinued therapy for AE: 2 due to acute renal failure which was progression coincident, 2 due to elevated creatinine suspected to be study drug related, and 1 for worsening on study of peripheral neuropathy (non-related). 1 patient died on study due to a cerebral vascular accident (assessed by the investigator as not study drug related). QT intervals (QTcF) were monitored per study protocol and out of >1500 post dose ECGs, 1 pt showed a Grade 2 prolongation of QTcF value above 480 ms, 2 pts had a QTcF increase of ≥60 ms compared to baseline, and 10 pts had a minimal 30–<60 ms increase of QTcF compared to baseline. A clinical durable response was observed in a 43-yr-old female patient, whose urine kappa light chain MM with bone lesions was progressing on lenalidomide/dexamethasone prior to enrollment. The patient had 5 prior lines of therapy, including auto-SCT twice (5 years apart), bortezomib, and thalidomide. Response was rapid, with a 60% reduction of urine M protein at Cycle 2 and 90% at Cycle 4. PR was confirmed in Cycle 7, including stabilized bone lesions, and is sustained at 11 months on therapy with urine light chain stable below the “measurable disease” level of 100mg/24hrs and urine IF still positive, thus a VGPR. A quick and dramatic reduction in angiogenesis markers (VEGF, sVEGFR1, and bFGF) was seen starting on Cycle 1, Day 8 of treatment, as well as a reduction (50%) of seric free light chain, which continued further throughout the later cycles. A second patient on study for >12 months is continuing to show clinical benefit after failing 10 prior lines of therapy (including Auto-SCT, bortezomib, lenalidomide, and thalidomide) and is maintaining MR. Stable disease observations of >3 months occurred in 3 pts. Single-agent, oral panobinostat at 20 mg/day thrice weekly was well tolerated and safe in this study. Evidence has since been obtained from clinical responses in patients with various hematological malignancies that higher doses of single-agent panobinostat can provide more optimal dosing schedules than the 20 mg dose. Thus, although the current study at the 20 mg schedule did not meet its objective, the observation of 1 durable VGPR and 1 durable and ongoing MR, in addition to transient disease stabilization in 3/38 patients, are encouraging results, especially at this low dose, warranting further clinical investigation of panobinostat. The analysis of final study results will be presented.

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Phase II trial of amrubicin in patients with previously treated small cell lung cancer (SCLC)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.7061 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 7061-7061 ◽

Cited By ~ 19

Author(s):

T. Kato ◽

H. Nokihara ◽

Y. Ohe ◽

N. Yamamoto ◽

I. Sekine ◽

...

Keyword(s):

Phase Ii ◽

Performance Status ◽

Single Agent ◽

Study Drug ◽

Survival Duration ◽

History Of ◽

Extensive Stage ◽

Previously Treated ◽

Grade 3 ◽

Minimax Design

7061 Background: Amrubicin, a totally synthetic 9-amino-anthracycline, has been shown to have excellent antitumor activity as a single agent against previously untreated extensive-stage SCLC. The objective of this study was to assess the efficacy and safety of amrubicin in patients with refractory or relapsed SCLC. Methods: Patients with histologically or cytologically confirmed SCLC, 20 to 74 years in age, performance status 0–2, with a history of receiving first- or second- line chemotherapy were eligible for the study. Amrubicin (45mg/m2/day) was administered on Days 1–3 every 3 weeks for four to six courses. The primary endpoint was the response rate (RR), and planned sample size for this phase II study was 33 patients (Simon’s two-stage minimax design). Results: From June 2003 to January 2005, 35 patients (26 males/9 females, median age, 64 years) were enrolled, and 34 of these patients were treated with the study drug. Four courses or more were administered in 59% (20/34) of the patients, and dose reduction was required in 52% (15/29) of the patients who had received 2 courses or more. Four complete responses and 14 partial responses were observed among the 34 treated patients, yielding a RR of 53% (95% confidence interval: 35.1%–70.2%). The median survival duration in the patients was 8.8 months, and the 1-year survival rate was 26%. Grade 3/4 leukopenia, neutropenia, and thrombocytopenia were observed in 76%, 97% and 38% of the patients, respectively. Febrile neutoropenia occurred in 12 patients (35%), and one patient died from treatment related pneumonia. Conclusion: Amrubicin (45mg/m2/day) was effective in patients with previously treated advanced SCLC, however, severe hematological toxicities occurred in some patients. No significant financial relationships to disclose.

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Phase II Study of the c-Met Inhibitor ARQ 197 (Tivantinib) in Patients with Relapsed Multiple Myeloma.

Blood ◽

10.1182/blood.v120.21.2976.2976 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2976-2976 ◽

Cited By ~ 1

Author(s):

Stephan Joseph Dorkhom ◽

Shadia Zaman ◽

Sheeba K. Thomas ◽

Raymond Alexanian ◽

Jatin J. Shah ◽

...

Keyword(s):

Multiple Myeloma ◽

Disease Progression ◽

Phase Ii ◽

Stable Disease ◽

Plasma Cells ◽

Phase Ii Study ◽

Single Agent ◽

Arq 197 ◽

Met Inhibitor ◽

Grade 3

Abstract Abstract 2976 Background: c-Met receptor tyrosine kinase (RTK) activity has been implicated in establishing the oncogenic phenotype across several human cancers with high levels of the activating c-Met ligand, hepatocyte growth factor (HGF). Malignant plasma cells secrete HGF-activator (HGFA), which converts HGF to its active form, and high HGF levels are correlated with a poor prognosis in multiple myeloma (MM). Syndecan 1 (CD138) on malignant plasma cells binds HGF and potentiates interleukin-6-induced growth and migration. HGF stimulation of myeloma cells also activates autophosphorylation of c-Met and other critical downstream signaling pathways promoting oncogenesis. Finally, pre-clinical studies have shown that suppression of c-Met signaling with a number of small molecules, including ARQ 197, induced myeloma cell apoptosis. Tevantinib-mediated cytotoxic response was observed at concentrations of less than 5 μM, which are achievable in the clinic. These findings supported the hypothesis that suppression of the HGF/c-Met signaling axis could be a rational strategy against relapsed multiple myeloma. Methods: In this phase II study, the efficacy and safety of ARQ 197, a non-competitive and highly selective inhibitor of the c-Met RTK, is being studied in patients with relapsed multiple myeloma. Primary objectives were to determine the overall response rate (ORR) to single-agent tivantinib in patients with relapsed multiple myeloma who had received one to four prior lines of therapy, and to define the toxicities in this population. ARQ 197 was administered at a starting oral dose of 360 mg twice daily with meals for each day of every 4-week treatment cycle. This dose was selected from prior phase I investigations in solid tumors, and at this dose level, steady-state plasma level sof ARQ-197 were 7 μM. Treatment could continue providing that patients did not experience undue toxicities, or disease progression. Tivantinib is provided through the Cancer Therapy Evaluation Program (CTEP), and this study is supported by CTEP, as well as the M. D. Anderson Cancer Center SPORE in Multiple Myeloma. Results: A total of 10 patients have been enrolled and treated to date, all of whom were evaluable for toxicity, with 8 evaluable for response based on having completed two treatment cycles. Patients had received from 1–3 prior lines of therapy for their disease, and 7/10 (70%) had presented with International Staging System stage I disease at diagnosis. All patients on study had an ECOG performance status of 1 or better, and received a median of 3.5 cycles of tivantinib (range 1–7). The most common adverse events (AEs) of any grade seen in at least 30% of patients included diarrhea (30%), dizziness (30%), dry eyes (30%), shortness of breath (30%), memory change (30%), myalgias (40%), fatigue (60%), and neutropenia (60%). Serious AEs (SAEs) occurred in 2 patients, including one patient with grade 3 syncope, and another with grade 4 neutropenia and a grade 3 anal fissure. Stable disease (SD) has been seen as the best response in 5/7 (71%) evaluable patients, which was maintained for up to 7 cycles, while the remaining patients showed evidence of disease progression. Conclusion: Enrollment is continuing to this first study of any c-Met inhibitor in patients with relapsed multiple myeloma to better define the role of single-agent tivantinib in this setting. To date, tivantinib has been tolerated well, and some evidence of activity has been seen, with stable disease in 63% of patients, all of whom were progressing at the time of enrollment. Updated toxicity and efficacy data will be presented at the time of the Annual Meeting. Correlative studies are also underway with the goal of identifying potential predictive biomarkers. Disclosures: Off Label Use: Tivantinib is being evaluated for patients with relapsed myeloma, but is not yet approved in this setting.

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Evaluation of Single Agent Lenalidomide in Patients with Newly Diagnosed Multiple Myeloma (NDMM).

Blood ◽

10.1182/blood.v114.22.3868.3868 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3868-3868

Author(s):

Rachid Baz ◽

Mohamad Hussein ◽

Daniel J. Lebovic ◽

Elizabeth Finley-Oliver ◽

Mehul P Patel ◽

...

Keyword(s):

Multiple Myeloma ◽

Median Time ◽

Light Chain ◽

Single Agent ◽

Immunomodulatory Activity ◽

High Dose ◽

Newly Diagnosed ◽

Antitumor Effects ◽

Grade 3

Abstract Abstract 3868 Poster Board III-804 Introduction Lenalidomide (Len) is an immunomodulatory drug with antitumor effects mediated through activation of T and NK cells as well as modulation of tumor cytokine environment. Currently Len is approved in combination with dexamethasone (dex) for treatment of patients with relapsed myeloma. Interestingly, in NDMM, higher 1 and 2 year survival rates were observed when the dose of dex was reduced compared to standard high dose dexamethasone and Len (Rajkumar et al. 2008). The immune suppressive effects of dex can antagonize Len immunomodulatory activity and may explain this observation. To our knowledge, Len has not been evaluated as a single agent in NDMM. Patients and methods Records of patients with newly diagnosed symptomatic multiple myeloma treated with single agent Len at H. Lee Moffitt Cancer Center and Roswell Park Cancer Institute were reviewed (after IRB approval at both institutions). Data was collected on disease characteristics, demographics and treatment outcomes. Responses assessed as per the IMWG criteria. Results From March 2007 to July of 2009, 18 patients with NDMM have been treated with Len alone. The median age was 70 years (range 46-84), and 12/18 were males. Heavy chain was IgG in 12 and IgA in 4 patients with 2 patients with light chain myeloma. The involved light chain was kappa in half the patients. Clinical stage of patients included stage IIIA (n=13), IIA (n=4) and IA (n=1) using the DS system whereas as per the ISS system 10, 6 and 2 has stages I, II and III respectively. Cytogenetics were not available on most patients (11); and 4 of 7 patients with available cytogenetics had deletion 13q identified by FISH. The median b2m was 2.8 mg/L (range 2.1-10.7) with >3.5mg/L in 7/18 patients. All except one patient (with a creatinine clearance of 49 ml/min) were started on Len 25 mg daily for 21 days of a 28 days cycle. As of August 1st 2009, 3 patients are inevaluable for response due to short follow up. Among the remainder 15 patients, 3 achieved a CR (1 stringent CR), 2 VGPR, 3 PR, 4 had MR with SD in additional 3 patients. Thus MR or better response was noted in 80% of patients. The median time to first response was 55 days (range 28-98) and median time to best response was 73 days (range 31-591). After a median follow up of 7 months (range 1-26), 1 patient died of progressive disease (despite the addition of dexamethasone and subsequent bortezomib therapy), 4 patients required the addition of dexamethasone. Len was generally well tolerated and no grade 4 hematologic toxicity were noted, 1 patient had grade 3 neutropenia, 1 patients grade 3 anemia and 2 patient grade 3 thrombocytopenia. Four patients had Len dose reduced. Conclusion Single agent Len appears to be an effective therapy in newly diagnosed myeloma patients (MR and better in 80% of patients) and should be evaluated in a prospective fashion in an attempt to decrease corticosteroid toxicity in a group of vulnerable patients and potentially enhance the immunomodulatory activity of Len. Our experience suggests that single agent Len can be effectively employed as an initial step in sequencing anti-myeloma regimen(s) for treatment of NDMM. Disclosures: Baz: celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: lenalidomide as a single agent in newly diagnosed myeloma. Hussein:Celgene: Employment.

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Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma

Blood ◽

10.1182/blood-2008-12-196238 ◽

2009 ◽

Vol 114 (4) ◽

pp. 772-778 ◽

Cited By ~ 110

Author(s):

Paul Richardson ◽

Sundar Jagannath ◽

Mohamad Hussein ◽

James Berenson ◽

Seema Singhal ◽

...

Keyword(s):

Multiple Myeloma ◽

Single Agent ◽

Progression Free Survival ◽

Prior Treatment ◽

Once Daily ◽

Free Survival ◽

Refractory Multiple Myeloma ◽

Treatment Regimens ◽

Common Grade ◽

Grade 3

Abstract Lenalidomide plus dexamethasone is effective for the treatment of relapsed and refractory multiple myeloma (MM); however, toxicities from dexamethasone can be dose limiting. We evaluated the efficacy and safety of lenalidomide monotherapy in patients with relapsed and refractory MM. Patients (N = 222) received lenalidomide 30 mg/day once daily (days 1-21 every 28 days) until disease progression or intolerance. Response, progression-free survival (PFS), overall survival (OS), time to progression (TTP), and safety were assessed. Overall, 67% of patients had received 3 or more prior treatment regimens. Partial response or better was reported in 26% of patients, with minimal response 18%. There was no difference between patients who had received 2 or fewer versus 3 or more prior treatment regimens (45% vs 44%, respectively). Median values for TTP, PFS, and OS were 5.2, 4.9, and 23.2 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (60%), thrombocytopenia (39%), and anemia (20%), which proved manageable with dose reduction. Grade 3 or 4 febrile neutropenia occurred in 4% of patients. Lenalidomide monotherapy is active in relapsed and refractory MM with acceptable toxicities. These data support treatment with single-agent lenalidomide, as well as its use in steroid-sparing combination approaches. The study is registered at http://www.clinicaltrials.gov as NCT00065351.

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Phase II Trial of Cetuximab With or Without Paclitaxel in Patients With Advanced Urothelial Tract Carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2012.41.9572 ◽

2012 ◽

Vol 30 (28) ◽

pp. 3545-3551 ◽

Cited By ~ 87

Author(s):

Yu-Ning Wong ◽

Samuel Litwin ◽

David Vaughn ◽

Seth Cohen ◽

Elizabeth R. Plimack ◽

...

Keyword(s):

Phase Ii ◽

Urothelial Cancer ◽

Single Agent ◽

Progression Free Survival ◽

Salvage Chemotherapy ◽

Free Survival ◽

Metastatic Urothelial Cancer ◽

Metastatic Setting ◽

Previously Treated ◽

Grade 3

Purpose The benefit of salvage chemotherapy is modest in metastatic urothelial cancer. We conducted a randomized, noncomparative phase II study to measure the efficacy of cetuximab with or without paclitaxel in patients with previously treated urothelial cancer. Patients and Methods Patients with metastatic urothelial cancer who received one line of chemotherapy in the perioperative or metastatic setting were randomly assigned to 4-week cycles of cetuximab 250 mg/m2 with or without paclitaxel 80 mg/m2 per week. We used early progression as an indicator of futility. Either arm would close if seven of the initial 15 patients in that arm progressed at the first disease evaluation at 8 weeks. Results We enrolled 39 evaluable patients. The single-agent cetuximab arm closed after nine of the first 11 patients progressed by 8 weeks. The combination arm completed the full accrual of 28 patients, of whom 22 patients (78.5%) had visceral disease. Twelve of 28 patients had progression-free survival greater than 16 weeks. The overall response rate was 25% (95% CI, 11% to 45%; three complete responses and four partial responses). The median progression-free survival was 16.4 weeks (95% CI, 12 to 25.1 weeks), and the median overall survival was 42 weeks (95% CI, 30.4 to 78 weeks). Treatment-related grade 3 and 4 adverse events that occurred in at least two patients were rash (six cases), fatigue (five cases), and low magnesium (three cases). Conclusion Although it had limited activity as a single agent, cetuximab appears to augment the antitumor activity of paclitaxel in previously treated urothelial cancers. The cetuximab and paclitaxel combination merits additional study to establish its role in the treatment of urothelial cancers.

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Efficacy and safety of nivolumab and trabectedin in pretreated patients with advanced soft tissue sarcomas (STS): Preliminary results of a phase II trial of the German Interdisciplinary Sarcoma Group (GISG-15, NitraSarc) for the non-L sarcoma cohort.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.11545 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 11545-11545

Author(s):

Daniel Pink ◽

Dimosthenis Andreou ◽

Anne Flörcken ◽

Alexander Golf ◽

Stephan Richter ◽

...

Keyword(s):

Phase Ii ◽

Single Agent ◽

Primary Efficacy ◽

Primary Efficacy Endpoint ◽

Efficacy And Safety ◽

Disease Stabilization ◽

Group A ◽

Pretreated Patients ◽

Grade 3 ◽

Group B

11545 Background: Single-agent PD-1 inhibitors have modest activity in the treatment of most STS. Potential strategies to increase efficacy include combination therapies targeting the tumor microenvironment. Considering that apart from direct growth inhibition and death of malignant cells, trabectedin (Tr) also induces macrophage depletion and/or different immunologic effects, suggesting a possible synergistic effect of combined Tr plus anti-PD-1 treatment. We therefore aimed to evaluate the efficacy and safety of combined Tr and nivolumab (Ni) as a second-line treatment in STS. Methods: The prospective, explorative, two group, non-randomized phase II NiTraSarc trial enrolled pretreated patients (pt) with advanced STS (Group A: lipo- or leiomyosarcomas, Group B: non-L-sarcomas). Pt were initially treated with 3 cycles of Tr 1.5 mg/m2, followed by the combination of Tr 1.5 mg/m2 + Ni 240 mg (“late combination cohort” (LCC)) for up to 16 cycles. After positive results of a preplanned interim analysis, pt received the combination therapy starting with cycle 2 (“early combination cohort” (ECC)). 92 pt were recruited to the trial (55 in Group A, 37 in Group B). Primary efficacy endpoint is progression-free survival rate after 6 months (PFSR6) according to RECIST v.1.1. This is a first analysis of the primary efficacy endpoint in Group B based on a modified intention-to-treat (mITT) population of evaluable 36 pt: 23 and 13 pt from the LCC and ECC, respectively. Results: The most common Group B subtypes comprised undifferentiated pleomorphic/not otherwise specified sarcoma (UPS/NOS, 13pt) and fibromyxoid sarcoma (FMS, 6pt). After a median follow-up of 5 months (m) PFSR6 was 13.9% for all pt, 8.7% in LCC and 23.1% in ECC. Median duration of disease stabilization (DoDS) was 4m in all pt, the LCC and the ECC. Two pt had a partial response (PR), 10 had disease stabilization (SD), while 13 pt progressed, and 11 had missing data. By subtype: PR- UPS/NOS=2 (DoDS 12.7m/12.5m). SD: UPS/NOS=3, epithelioid=2, synovial=2, FMS=1, fibrosarcoma=1, other=1. All 36 pt experienced at least one adverse event (AE) reaching a total of 579 AEs, 141 (24.4%) of which were considered to be grade ≥3 treatment-related AEs. The main grade ≥3 AEs were: leukopenia (47.2% of pt), neutropenia (41.7% of pt), thrombocytopenia (33.3% of pt), increased ALT (30.6% of pt), and anemia (27.8% of pt). Conclusions: Tr+Ni was well tolerated and showed activity in at least some patients with non-L-sarcomas (mostly UPS/NOS) especially in the ECC. Analyses of the collected data, including PD-L1 expression profile, with the goal to establish whether Tr+Ni should be further pursued in these patients, are ongoing. ClinicalTrials.gov Identifier: NCT03590210; EudraCT: 2017-001083-38. Clinical trial information: NCT03590210.

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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.

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Carfilzomib Thalidomide and Dexamethasone Is Safe and Effective in the Treatment of Relapsed/Refractory Multiple Myeloma: An Open Label Phase II Australasian Leukaemia and Lymphoma Group (ALLG) MM 018/ Asian Myeloma Network (AMN) 002 Study

Blood ◽

10.1182/blood-2020-139174 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Hang Quach ◽

Simon J Harrison ◽

Je-Jung Lee ◽

Nichloas Murphy ◽

Jae Hoon Lee ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Board Of Directors ◽

Phase Ii ◽

Primary Endpoint ◽

Research Funding ◽

Open Label ◽

Advisory Committees ◽

Open Label Phase ◽

Grade 3

Background: The combination of carfilzomib with immunomodulatory drugs (IMiDs) and dexamethasone is active in multiple myeloma (MM). Carfilzomib, thalidomide, and dexamethasone (KTd) has been studied in upfront MM treatment but has not been studied in the setting of relapsed/refractory myeloma (RRMM). The ALLG MM018/ AMN002 is an open-label phase II study of KTd in patients with RRMM. This study was conducted across 16 sites across Australia, New-Zealand, Singapore, South Korea and Taiwan. Method: Patients with RRMM with 1-3 prior lines of treatment were given carfilzomib [K: 20mg/m2 IV cycle 1 days 1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from cycle 1 day 8 onwards], thalidomide (T: 100mg po nocte) and dexamethasone [dex: 40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, T was omitted, and K was given on days 1,2,15,16 and dex days 1,15 every 28-day cycles for a further six cycles. The primary endpoint was PFS. Secondary endpoints were ORR, overall survival, adverse events, and quality of life (QoL). The study had an 80% power to detect a ≥70% PFS at 6.5 months compared to historical ≤50% PFS at 6.5 months expected with Td (Kropff, M. et al. Haematologica 2012), at a significance level of 0.05. Results: This study has completed accrual. Eighty-three patients [median age of 66 years (42-85)] were enrolled with a median follow up of 15.9 (0.9-26) months. ORR rates were 86.4% (≥VGPR 70.2%). Median PFS was 20m (95% CI 15.9-26m). PFS at 6.5 months was 76.2% (95% CI 73.6-84.9%). Median OS has not been reached, and was 75% at 20 months. The most common grade ≥3/4 AEs were peripheral neuropathy (16%), upper respiratory tract infections (12%), dyspnoea (14%), and hypertension (10%). Grade ≥3/4 cardiac AEs occurred in 6%. The median carfilzomib dose that was delivered was 70.7% (32.8-92.6%) of the target dose. Thus far, 41% of patients have completed the intended 18 cycles of treatment. 21% of patients ceased therapy early. The most common reason for early treatment cessation was disease progression (30%) and adverse events (15%). Fifteen patients (18%) have died, 11 were due to MM, two from infection, one from an ischaemic cardiac event, and one from a traffic accident. QoL, as measured by the EQ-5D-5L instrument, remained stable throughout treatment. Conclusion: The ALLG MM018/AMN 002 study has met its primary endpoint. The KTd schedule as outlined in this study is efficacious in patients with RRMM, resulting in a prolonged PFS and a safety profile in line with previous reports for each of carfilzomib and thalidomide. KTd is an active option in jurisdictions where the cost of other IMiDs prohibits regulatory funding. Comparisons of efficacy and adverse events between the Caucasian and Asian populations will be presented at the meeting. Disclosures Quach: Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Haemalogix: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Soo:Hanmi: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

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DEDUCTIVE: A study of tivozanib in combination with durvalumab in subjects with untreated advanced hepatocellular carcinoma—Phase Ib results.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.294 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 294-294

Author(s):

Renuka V. Iyer ◽

Daneng Li ◽

Farshid Dayyani ◽

Alexandria T. Phan ◽

Michael N. Needle ◽

...

Keyword(s):

Patient Outcomes ◽

Phase Ii ◽

Single Agent ◽

Objective Response ◽

Primary Objective ◽

Advanced Hepatocellular Carcinoma ◽

Cross Sectional ◽

Advanced Hcc ◽

Grade 3 ◽

Improve Patient

294 Background: A recent ph3 study combining bevacizumab (VEGF-A Mab) with atezolizumab (PD-L1 inhibitor) has shown significant improvements in OS and PFS demonstrating that a combination of VEGF and PDL1 inhibition can improve patient outcomes over sorafenib. Tivozanib (T, a potent and selective VEGFR 1, 2 & 3 TKI) and durvalumab (D, a PD-L1 antibody) have both demonstrated single agent activity in HCC and have been combined safely with other therapies. T blocks all three VEGF receptors, and when combined with a PD-L1 inhibitor may improve patient outcomes. The ph1 portion of this study combines T with D to establish the recommended phase II dose (RP2D) and provide preliminary safety and efficacy data. Methods: Major eligibility criteria are adults with documented advanced HCC, Child-Pugh Class A, ECOG 0 or 1, creatinine clearance > 40 ml/min. Major exclusion criteria are co-infection with HBV and HCV and significant organ dysfunction. The starting dose is the combination of T 1 mg orally for 21 days followed by 7 days off treatment and D 1500 mg intravenously every 28 days. A DLT is generally defined as the occurrence of any Grade ≥3 immune or non-immune adverse event (AE) in Cycle 1 that is at least possibly related to the investigational regimen other than any grade of vitiligo or alopecia or Grade 3 controllable hypertension in cycle 1. The primary objective is to establish the RP2D and the safety and tolerability for this combination in patients with advanced HCC. Patients will be treated until progression of disease, unacceptable side effects, or death. Outcome measures will be AEs per CTCAE v.5 and cross-sectional imaging performed every 8 weeks. Results: Seven patients were enrolled in phase I. Six were male; the median age was 75 (range 40 to 82). One patient had mild elevation of LFTs and did not complete the 21-day course of T and was replaced. No patient experienced a >=grade 3 AE in cycle 1. The most common AEs, each seen in two of seven patients, were anorexia, cough, diarrhea, dysphonia, fatigue, hypertension, and palmar-plantar erythrodysesthesia. Two of seven have achieved a partial response. Conclusions: The combination of T with D in patients with untreated advanced HCC is well tolerated. The RP2D for the combination is T 1 mg orally for 21 days on treatment followed by 7 days off treatment and D 1500 mg intravenously every 28 days. In the phase II portion of the study an additional 30 patients will be treated at the RP2D. Secondary objectives are to assess the objective response rate, progression free survival, and overall survival in this population. Clinical trial information: NCT03970616.

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