Phase 1/2 Trial Of Lenalidomide In Combination With Cyclophosphamide and Prednisone (REP) In Patients With Lenalidomide-Refractory Multiple Myeloma (REPEAT-study)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 287-287 ◽  
Author(s):  
Inger S. Nijhof ◽  
Sonja Zweegman ◽  
Mark-David Levin ◽  
Harry R. Koene ◽  
Aart Beeker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Dose Level ◽  
Research Funding ◽  
Phase 1 ◽  
Oral Cyclophosphamide ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Grade 3 ◽  
Dose Levels

Abstract Background The outcome of multiple myeloma (MM) patients who are no longer responding to thalidomide, lenalidomide (LEN) and bortezomib (BORT) is very poor, with a median event-free survival of 5 months and median overall survival (OS) of 9 months (Kumar SK et al, Leukemia 2012; 26;149-157). We have previously shown in a small retrospective study that the combination of continuous low dose oral cyclophosphamide (endoxan) and prednisone combined with lenalidomide (REP) had remarkable activity in heavily pretreated LEN-refractory multiple myeloma patients (median 6 lines of previous chemotherapy) (vd Donk et al; Br J Haematol 2010;148(2):335-7). To determine the optimal dose of lenalidomide with continuous cyclophosphamide and prednisone, we initiated a prospective study to evaluate the maximum tolerated dose (MTD) of the REP regimen and to assess its efficacy and safety in LEN-refractory MM patients. Here we report safety and efficacy data from the phase 1 dose-escalation part of the REPEAT-study (NCT01352338). Patients and Methods Patients aged ≥ 18 years with LEN-refractory MM, ECOG-performance status 0-3 and adequate kidney, liver and hematologic function were included. Five dose levels were evaluated using a standard 3+3 design, based on dose-limiting toxicities (DLTs) occurring in cycle 1. Patients received LEN in doses ranging from 10-25 mg/day on days 1-21 of 28-day cycle, while oral cyclophosphamide (50 or 100 mg) and prednisone (20 mg) were given continuously. Therapy was continued until progression. The MTD for the phase 2 part is defined as the highest dose level with 0 or 1 DLT's observed in 6 patients. Results Up till now, 35 patients were enrolled (22 in phase 1 and 13 in phase 2) from August 2011 to June 2013. The phase 2 part is still recruiting and data are not evaluable yet. One patient in phase 1 was excluded because of study violation and is not included in the analysis. The median age of the 21 evaluable patients in phase 1 was 69 years (range 41-73); 76% were male. The median duration of the disease from diagnosis was 41 months (range 18-96), median number of prior therapies was 3 (range 2-6), and 12 patients (57%) had previously received autologous SCT. All patients were LEN-refractory, 19 (90%) had prior BORT treatment, and 16 (76%) had BORT-refractory MM. Fifty-five % of the patients were considered high risk by FISH. At the time of analysis, 16 of 21 patients in phase 1 have discontinued treatment because of disease progression (13), alternative treatment (allo-SCT) (1), or adverse events (2). The MTD was defined as LEN 25 mg days 1-21 of a 28-day cycle, combined with oral cyclophosphamide 50 mg and prednisone 20 mg continuously (dose level 4), based on three patients experiencing a DLT: two developed pneumonia (in dose levels 4 and 5; CTC grade 3), and one patient at dose level 5 experienced CTC grade 3 dyspnea. Neutropenia (18%) and thrombocytopenia (18%) were the most common grade 3 hematological adverse events (AEs), which were managed with growth factor support and/or dose modification. There were no grade 4 hematologic AEs. Grade 3 respiratory tract infections (29%) and grade 2 fatigue (19%) were the most common non-hematological AEs. Venous thromboembolism occurred in 1 patient. Figure 1 shows a waterfall plot of the responses of the patients that participated in the phase 1 part of the study. Overall response rate (≥ PR) was 67% with 6 out of 21 (29%) patients achieving at least VGPR. In addition 2 patients achieved MR (≥ MR: 76%). Median PFS and OS were 6.3 and 15.5 months respectively. Similar results were achieved in the subset of patients with LEN- and BORT-refractory disease. Interestingly, laboratory experiments with purified myeloma cells from these patients suggest synergism between LEN and cyclophosphamide. Conclusions The REP regimen induces high response rates and prolonged PFS and OS in LEN-refractory patients with acceptable toxicity. The MTD is defined as LEN 25 mg days 1-21 of a 28-day cycle, combined with oral cyclophosphamide 50 mg and prednisone 20 mg continuously. Phase 2 is enrolling patients and evaluates efficacy and safety of the REP regimen at the MTD. REP should be considered a valuable salvage option for LEN-refractory MM patients. We will present an updated follow-up at ASH. Disclosures: Sonneveld: Onyx: Research Funding; Millenium: Research Funding; Janssen-Cilag: Research Funding; Onyx: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Celgene: Research Funding. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria. van de Donk:Celgene: Research Funding.

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1723-1723
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Peter Anglin ◽  
Christine Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Oral Cyclophosphamide ◽  
Varicella Zoster ◽  
Refractory Multiple Myeloma ◽  
Grade 3 ◽  
Dose Levels

Abstract Oral cyclophosphamide and prednisone is a convenient regimen in relapsed and refractory multiple myeloma (MM), with a partial response (PR) rate of 40% and median progression-free survival of 19 months in our retrospective analysis of patients in first or second relapse after autologous stem cell transplantation (ASCT) (Trieu Y, et al, Mayo Clin Proc2005; 80: 1582). We sought to enhance the efficacy of this regimen by adding oral lenalidomide (Revlimid®), a potent anti-myeloma agent, in a phase I-II trial. The CPR regimen consisted of cyclophosphamide on days 1, 8 and 15, lenalidomide on days 1–21, and prednisone 100 mg every other day in a 28-day cycle. ASA 81 mg/day was given to all patients (pts) as prophylaxis for DVT. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007–07/2008, 15 pts with relapsed/refractory MM were entered onto study. Median age was 60 (45–78) years and 60% were male. Immunoglobulin subtype was IgGκ:λ in 10:1; IgA κ:λ in 2:1 and κ light chain in 1. Median number of prior regimens was 2 (1–3) and 14 had undergone previous ASCT, including double transplants in 2 pts. Prior therapy also included thalidomide in 3 (20%) and bortezomib in 6 (40%). FISH cytogenetics were available in 9, but none had 13q deletion, t(4;14) or p53 deletion. At the time of protocol entry, median β2-microglobulin level was 222 (92–325) nm/L, albumin 38 (35–46) g/L, creatinine 78 (50–100) μmol/L, platelet count 230 (93–318) x 109/L and ANC 2.5 (1.9–9.0) x 109/L. Protocol treatment is summarized in Table 1. Dose level N Cyclophosphamide dose (mg/m2) Lenalidomide dose (mg) Prednisone dose (mg) Median # cycles given 1 3 150 15 100 9 2 3 150 25 100 6 3 6 300 25 100 4 3 (expanded) 3 300 25 100 1 Dose limiting toxicity was not observed during cycle 1 at any of the dose levels and the maximum tolerated dose of this regimen has not yet been reached at the highest dose level planned; all pts remain on active therapy. Grade 3/4 thrombocytopenia was seen in 1 pt (cohort 2) and neutropenia in 4 pts (1 in cohort 1, 1 in cohort 2 and 2 in cohort 3) and were managed with dose reduction and/or growth factor support. No episodes of febrile neutropenia occurred in any pt. Only 1 pt experienced varicella zoster; routine antiviral prophylaxis was not used. Other grade 3/4 non-hematologic toxicities were uncommon and included abdominal pain/bacteremia in 1 pt in cohort 1, hypokalemia in 1 pt in cohort 2, and DVT in 1 pt in cohort 3. Mild grade 1/2 constipation (47%), muscle cramps (33%) and fatigue (33%) were also noted. To date, best response includes the following: dose level 1 (1 near complete remission [nCR], 2 PR); dose level 2 (3 PR); dose level 3 (4 PR, 2 minimal response [MR]); expanded cohort 3 (1 MR, 2 too early). We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28-day cycle with minimal toxicity; 2) the overall response rate (nCR + PR + MR) in 13 evaluable pts to date is 87%; 3) no pts have progressed in this preliminary analysis; 4) longer follow-up is required to assess the long-term efficacy of this regimen.

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1874-1874 ◽  
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Saima Dean ◽  
Peter Anglin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Oral Cyclophosphamide ◽  
Refractory Multiple Myeloma ◽  
Grade 3

Abstract Abstract 1874 Poster Board I-899 Lenalidomide (Revlimid®) and dexamethasone is an effective regimen in relapsed/refractory multiple myeloma (MM) patients (pts), with an overall response rate of 60.6% and median time to progression (TTP) of 13.4 months (Dimopoulos MA, et al, Leukemia 2009 Jul 23 [Epub ahead of print]). Oral cyclophosphamide and prednisone is an older regimen with excellent patient tolerance, and we sought to enhance the efficacy of lenalidomide by adding oral cyclophosphamide and prednisone in this phase I-II trial. The CPR regimen consisted of cyclophosphamide on days 1, 8 and 15; lenalidomide on days 1–21; and prednisone 100 mg every other day in a 28 day cycle. ASA 81 mg/day was given to all pts as DVT prophylaxis. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007–07/2009, 31 pts with relapsed/refractory MM who had not previously received lenalidomide were entered onto study. Median age was 61 (40–78) years and 61% were male. Immunoglobulin subtype was IgG in 19 pts (61%), IgA in 8 pts (26%) and light chain only in 4 pts (13%). Median number of prior regimens was 2 (1–5) and 28 pts had undergone previous ASCT, including double transplants in 6 pts. Prior therapy included thalidomide in 9 (29%) and bortezomib in 15 (48%). FISH cytogenetics were available in 13 pts; one had 13q deletion but none had t(4;14) or p53 deletion. At the time of protocol entry, median β 2-microglobulin level was 246 (92–767) nm/L, albumin 39 (34–48) g/L, creatinine 83 (50–126) μmol/L, platelet count 230 (75–337) × 109/L and ANC 2.5 (1.1–6.1) x 109/L. Protocol treatment is summarized in Table 1. Dose limiting toxicity was not observed during cycle 1 at any dose level. Grade 3–4 toxicities included thrombocytopenia in 5 pts (16%) and neutropenia in 9 pts (29%). These were managed with dose reduction and/or growth factor support. Four episodes of febrile neutropenia occurred. Other grade 3–4 non-hematologic toxicities included abdominal pain/bacteremia in 1 pt in cohort 1; hypokalemia in 1 pt in cohort 2; and DVT in 2 pts, dizziness in 2 pts and fatigue in 1 pt in cohort 3. Using the International uniform response criteria (Durie BG, et al, Leukemia 2006; 20:1467–1473), the best response was documented at a median of 6 (1–5) cycles and included the following: dose level 1 (1 CR, 2 PR); dose level 2 (1 VGPR, 2 PR); dose level 3 (5 CR, 9 VGPR, 9 PR, 1 MR and 1 stable disease). At a median follow-up (F/U) of 12 (8–21) months, 20 pts remain on study, 2 have withdrawn and 9 pts have progressed at a median of 9 (4–13) months; only 1 one has died (due to MM). We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28 day cycle with minimal toxicity; 2) the overall response rate (CR + VGPR + PR) in 31 pts to date is 93%; 3) at a median F/U of 1 year, only 9 pts (29%) have progressed; 4) longer follow-up is required to assess the TTP and survival of the CPR regimen. Disclosures: Reece: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Lenalidomide in combination with drugs other than dexamethasone. Anglin:Celgene: Honoraria. Chen:Celgene: Honoraria, Research Funding. Kukreti:Celgene: Honoraria. Mikhael:Celgene: Honoraria. Trudel:Celgene: Honoraria.

Escalated Dose Bortezomib Once Weekly Combined with Lenalidomide and Dexamethasone (eVRD) Followed by Lenalidomide Maintenance in First Relapse of Multiple Myeloma (MM). the HOVON 86 Phase 2 Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1853-1853
Author(s):  
Pieter Sonneveld ◽  
Okke de Weerdt ◽  
Mark-David Levin ◽  
Wendimagegn Ghidey ◽  
Edo Vellenga ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 2 ◽  
Level 3 ◽  
First Relapse ◽  
Grade 3 ◽  
Dose Levels

Abstract Abstract 1853 Background: Bortezomib (1.3 mg/m2) combined with Lenalidomide (10–25 mg) and Dexamethasone (VRD) is effective in newly diagnosed and relapsed multiple myeloma (MM). Reported data on the effect of these drugs in relapse/refractory MM are available from the APEX and MM-009/MM-010 trials, respectively. These trials, however, were performed in patients with 2–8 prior regimens. Aim: This investigator sponsored two-step phase 2 HOVON trial was designed to evaluate escalated dosages of Bortezomib (B) given once weekly and daily Lenalidomide (L) combined with weekly Dexamethasone (D) (eVRD) followed by Lenalidomide maintenance in an homogenous group of patients with symptomatic MM in first relapse. The goal was to explore the maximum tolerated dose of this combination in order to achieve a durable second remission. Methods: Dose levels were B 1.3 mg/m2, L 10 mg, (level 1); B 1.6 mg/m2, L 10 mg (level 2); B 1.6 mg/m2, L 15 mg (level 3); B 1.6 mg/m2, L 20 mg (level 4). D dose was 20 mg days 1–2, 8–9, 15–16 in all dose levels. Inclusion criteria were symptomatic MM ISS stage 1–3, aged 18–80 in first relapse after initial treatment. The primary endpoint was response (complete response (CR) according to IMWG criteria, very good partial response (VGPR), partial response (PR), together overall response (ORR)) with Progression-free Survival (PFS), overall survival (OS) and toxicity as secondary endpoints. Results: Eighty-one patients were included, i.e. 15 patients in dose levels 1, 2 and 3, followed by 66 in the phase 2 part. This report is based on 12 patients in the dose escalation phase and the first 42 patients in the phase 2 part. Median age was 67 yrs, with ISS stages 1 (56%), 2 (40%) and 3 (5%). 37/54 patients had received HDM followed by stem cell transplant as part of first-line treatment. The MTD was reached at dose level 3 when the maximum of 3 SAEs in 5 patients was observed. After establishment of the MTD, the phase 2 part of the trial was performed with B 1.6 mg/m2 once weekly for 3 weeks, L 20 mg days 1–21 and D 20 mg days 1–2, 8–9, 15–16, for 8 cycles of 28 days followed by L maintenance 10 mg days 1–21 of a 28 days cycle. The median number of cycles was 6 in the dose-escalation phase and 7 cycles in phase 2. 7/12 (58%) patients in the dose-escalation phase and 23/42 (55%) patients in phase 2 started lenalidomide maintenance. Reasons for premature discontinuation of the protocol treatment were toxicity (14%), progression (24%), no response (5%) or other (14%). Polyneuropathy grade 3–4 occurred in 19% with a median time to maximum PNP of 123 days. Hematological toxicity grade 3 and 4 was observed in 29 % of patients In the phase 2 part including 42 patients the ORR was 92 %, ≥VGPR 64% and CR/nCR 30%. Median time to response was 1.1 cycles. At a median follow-up of 13.6 months PFS at 18 months was 52% and OS 76%. Among predetermined risk factors ISS stage, prior HDM/ASCT and achieved response on protocol, depth of response was the only significant factor which was associated with PFS (p<0.001) and OS (p<0.001), Eight patients died from progressive MM (n=4) or other causes (n=4). One second primary malignancy was observed in dose level 3. Conclusions: Escalated VRD followed by Lenalidomide maintenance is effective and feasible in patients with first relapse MM. We will present an updated follow-up at ASH This trial was registered as Eudract nr 2007–002533–37. Unrestricted grants and study drug were provided by Janssen and Celgene. Disclosures: Sonneveld: Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Onyx: Honoraria, Research Funding.

Phase I/II, Multicenter, Open-Label, Dose-Escalation Study of Bendamustine in Combination with Lenalidomide and Dexamethasone (BRD) in Patients with Relapsed Multiple Myeloma: A Multiple Myeloma Research Consortium Study.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2965-2965
Author(s):  
Shaji K. Kumar ◽  
Amrita Krishnan ◽  
Vivek Roy ◽  
Todd M Zimmerman ◽  
Morie Abraham A Gertz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Expert Testimony ◽  
Research Funding ◽  
Phase 1 ◽  
Response Rates ◽  
Hematological Toxicity ◽  
Phase 2 ◽  
Dose Reductions

Abstract Abstract 2965 Background: Alkylating agents have been the mainstay of multiple myeloma (MM) therapy for decades and despite introduction of several new therapies, it continues to play a significant role in its management as part of various drug combinations. While melphalan has been the most commonly used alkylator in MM, recent studies have suggested significant activity for bendamustine, a bifunctional alkylator. The combination of lenalidomide and melphalan has been associated with high response rates in relapse and newly diagnosed MM. Based on these promising results we designed a trial to evaluate the maximally tolerated dose of lenalidomide and bendamustine when used in combination as well as the efficacy of the combination in relapsed disease. Patients and Methods: Patients with relapsed MM and measurable disease were enrolled on this phase 1/2 trial provided they had not more than 4 prior lines of therapy for MM, had adequate performance status and organ and hematological function. Patients refractory to lenalidomide were allowed to enroll. The primary objectives were to (i) to determine the MTD of bendamustine and lenalidomide in combination with dexamethasone in subjects with relapsed MM (phase 1) and (ii) to evaluate the confirmed response rate of bendamustine in combination with lenalidomide and dexamethasone in patients with relapsed MM (phase 2). Bendamustine (B) was administered on days 1 and 2 of a 28-day cycle at doses of 50–100 mg/m2. Lenalidomide (R) was given days 1–21 at doses of 15–25 mg daily. Dexamethasone (D) was administered at 40 mg weekly. Dose escalation was done using a 3+3 design and MTD was defined as one dose level below that resulted in >=2 DLTS among 6 patients. The primary end point for this trial was the proportion of patients with confirmed hematologic response (sCR, CR, VGPR, or PR) over the first 6 cycles of treatment. Results: A total of 72 patients were accrued to this study from March 2010 to May 2012: 21 patients in phase 1 and 51 in phase 2. The 6 patients from the MTD dose level of phase 1 were also included in phase 2. The median age of all 72 patients was 62.1 (range, 40–86) and 57% were male. Majority (75%) of patients had previously been exposed to lenalidomide and 69% had prior exposure to bortezomib. Median # of prior therapies was 3 (range, 1–5) and 74% of patients had a prior autologous stem cell transplant. Patients have received a median of 4 cycles (range, 1–25), with 27 patients still continuing on active treatment. Disease progression led to study discontinuation in 22 (49%) and adverse events were the reason for discontinuation in 14 (31%). In phase I, two DLTs (Grade (Gr) 2 neuropathy and Gr 4 neutropenia) were seen at the highest dose level (100 mg/m2 B, 25 mg R), and the MTD was determined as 75 mg/m2 of B given days 1 and 2 and 25 mg of R days 1–21, along with D 40 mg weekly. Overall patients, 12/21 (57%) had a PR or better. In phase 2, 17 (40%) confirmed responses (>=PR) were seen among the 43 patients evaluable for response (received at least 6 cycles of treatment or have gone off study prior to 6 cycles); including 9 (21%) VGPR and 8 (19%) PR. An additional 5 patients had a minor response. Over all dose levels, a gr 3 or higher adverse event at least possibly attributed to the study was seen in 75% of patients. The most common toxicities were all hematological (thrombocytopenia and leukopenia), and most common non-hematological toxicity was infection. Prolonged time to recovery of blood counts was seen in a few patients, but majority of patients were able to tolerate the regimen with adequate dose reductions. Conclusion: The recommended dose of the combination for further studies is bendamustine at 75 mg/m2 days 1 and 2, lenalidomide 25 mg daily on days 1–21 and dexamethasone days 1, 8, 15, 22; with cycles repeated every 28 days. The regimen is well tolerated with hematological toxicity being the most common and manageable with dose reductions. The regimen is effective with high response rates and durable responses seen. Updated results with response rates and time to event analyses will be available for the entire cohort at the time of meeting. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Cephalon: Research Funding; Genzyme: Research Funding. Krishnan:celgene: Consultancy, Speakers Bureau. Zimmerman:Celgene: Honoraria; Millennium: Honoraria; Novartis: Expert Testimony, Expert Testimony Other. Vij:Teva: Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Millennium: Speakers Bureau; Onyx: Honoraria, Research Funding.

scholarly journals Combination Treatment of the Bruton's Tyrosine Kinase Inhibitor Ibrutinib and Carfilzomib in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Initial Results from a Multicenter Phase 1/2b Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 377-377 ◽  
Author(s):  
Ajai Chari ◽  
Saurabh Chhabra ◽  
Saad Usmani ◽  
Sarah Larson ◽  
Ruben Niesvizky ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Tyrosine Kinase ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Phase 2 ◽  
Advisory Committees ◽  
Bruton's Tyrosine Kinase ◽  
Grade 3

Abstract Background: Recent advances have improved outcomes for patients (pts) with multiple myeloma (MM); however, novel agents targeting different pathways are still needed. Ibrutinib (ibr) is a first-in-class, once-daily, oral, covalent inhibitor of Bruton's tyrosine kinase (BTK), an enzyme overexpressed in malignant plasma cells, whose expression may positively regulate the myeloma stem cell-like population (Yang 2015). Clinical activity was observed at the 840-mg dose of ibr in heavily pretreated pts with relapsed or relapsed/refractory MM (RRMM), when combined with weekly dexamethasone (dex) (Vij 2014). Furthermore, BTK-mediated upregulation of NF-κB p65 contributes to proteasome inhibitor (PI) resistance in MM cell lines; thus, BTK inhibition with ibr may help overcome PI resistance (Murray 2015). In vitro, ibr has demonstrated synergy with PIs in MM (Rushworth 2013) and mantle cell lymphoma cells (Ou 2013). PCYC-1119 (NCT01962792) is an ongoing phase 1/2b study of ibr + carfilzomib (CFZ) ± dex in RRMM. Methods: Eligible pts received ≥2 prior therapies, including bortezomib (BTZ) and an immunomodulatory agent (IMiD) and had either no response or documented disease progression following the most recent treatment. Dose escalation followed a 3+3 design, followed by expansion of 2 cohorts (Table). Phase 1 primary objectives were maximum tolerated dose/recommended phase 2 dose (RP2D) determination and safety. Results: As of July 8, 2015, 40 pts were enrolled and received ibr combined with CFZ ± dex across multiple dose levels during the phase 1 portion. No dose-limiting toxicities (DLTs) were observed, and cohorts 2b and 3b were chosen for expansion to further evaluate safety and efficacy. Pts had a median age of 63 y (range, 44-83) and a median time from diagnosis of 4.3 y (range, 0.5-25.3). Cytogenetic assessment by FISH identified that 20% and 8% of pts had t4;14 and del17p, respectively. Overall, pts received a median of 3 prior lines of therapy (range, 2-11), including 10% prior CFZ, 25% pomalidomide, 25% thalidomide, 73% autologous stem cell transplant, and 100% BTZ and lenalidomide. Moreover, 88% of pts were refractory to their last therapy, with 73% refractory to BTZ, 73% refractory to lenalidomide, and 58% refractory both to IMiD and PI. No relevant differences were observed across cohorts. Thirty-six pts were evaluable for efficacy. With early follow-up, the initial objective response rate (ORR) was 58% and the clinical benefit rate (CBR) was 67%. In cohort 3b, the ORR and CBR were 65% and 77%, respectively, including 3 very good partial responses (VGPRs) and 1 stringent complete response (sCR). No clinically meaningful tolerability differences were seen between cohorts, and no new safety findings were observed. Across all cohorts, the most common all-grade nonhematologic adverse events (AEs) were diarrhea (43%), cough (35%), constipation and fatigue (30% each), and nausea (28%). Grade ≥3 hematologic AEs included thrombocytopenia (15%), anemia (13%), and neutropenia (5%). Grade ≥3 nonhematologic AEs occurring in ≥10% of pts were pneumonia and hypertension (15% each), diarrhea (13%), and fatigue (10%). Eleven pts reported treatment related SAEs. No clinically relevant differences in AEs were observed across cohorts. Ten pts discontinued study treatment due to progressive disease; an additional 6 pts discontinued due to an AE, and 6 pts discontinued due to investigator or pt decision. Duration of treatment ranged from 0.3 to 13.6 months, and 17 pts remain on treatment. Updated data will be presented. Conclusions: The initial phase 1 data indicated promising clinical potential for ibr + CFZ + dex, as it is well tolerated with no DLTs, no new toxicities, and no increase in the severity of known toxicities for the individual agents. The preliminary ORR of 58%, with 1 sCR and 3 VGPRs in cohort 3b, is encouraging in this mostly refractory patient population, especially with the high number refractory to BTZ. Cohort 3b was established as the RP2D and will be further evaluated in the phase 2 portion of the study. Table. Dosing Cohorts Cohort ibr* mg/qd CFZ† mg/m2 dex‡ mg 1(n=3) 560 20/27 - 2a(n=5) 560 20/36 - 2b(n=14) 560 20/36 20 3b(n=18) 840 20/36 20 *Starts on Day (D) 8 of Cycle (C) 1; continuous thereafter. †D1-2, 8-9, 15-16 through C12; thereafter D1-2, 15-16. ‡D1-2, 8-9, 15-16, 22-23; 10 mg for pts age ≥75 y; 4 mg prior to CFZ during C1 only (cohorts 1 and 2a) with re-initiation as needed. Disclosures Chari: Novartis: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Array: Consultancy, Research Funding. Off Label Use: ibrutinib in relapsed or relapsed/refractory MM. Usmani:Celgene: Consultancy, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Research Funding, Speakers Bureau; Array BioPharma: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Novartis: Speakers Bureau. Larson:BMS: Consultancy. Niesvizky:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Consultancy, Honoraria, Research Funding, Speakers Bureau. Matous:Celgene: Consultancy, Speakers Bureau; Millenium: Speakers Bureau; Onyx: Speakers Bureau. Gasparetto:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Holkova:Seattle Genetics, Inc.: Research Funding. Lunning:TG Therapeutics: Consultancy; Gilead: Consultancy; Spectrum: Consultancy; Genentech: Consultancy; Celgene: Consultancy; BMS: Consultancy; Juno: Consultancy; Onyx: Consultancy. Valent:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Anderson:Celgene: Speakers Bureau; Onyx: Speakers Bureau; Takeda: Speakers Bureau. Kwei:Pharmacyclics LLC, an AbbVie Company: Employment. Chang:Pharmacyclics LLC, an AbbVie Company: Employment. Graef:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Bilotti:Pharmacyclics LLC, an AbbVie Company: Employment. McDonagh:Pharmacyclics LLC, an AbbVie Company: Research Funding; Sanofi: Research Funding; Onyx: Research Funding; Karyopharm: Research Funding.

A phase I/II investigation of nivolumab and ABI-009 (nab-sirolimus) in advanced undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), chondrosarcoma (CS), osteosarcoma (OS), and Ewing sarcoma: Preliminary efficacy and safety results.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 11057-11057 ◽  
Author(s):  
Erlinda Maria Gordon ◽  
Victoria S. Chua-Alcala ◽  
Katherine Kim ◽  
Rekha Baby ◽  
Nicole Angel ◽  
...  
Keyword(s):  
Dose Level ◽  
T Cell Activation ◽  
Ewing Sarcoma ◽  
Mtor Inhibitor ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Synergistic Activity ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Grade 3

11057 Background: Immune checkpoint inhibitors that promote sustained T cell activation may have synergistic activity with an mTOR inhibitor. This phase 1/2 study is aimed to investigate if ABI-009 a novel albumin-bound mTOR inhibitor is feasible and improve clinical outcomes in combination with nivolumab. Methods: Eligible patients with advanced UPS, LPS, CS, OS, or Ewing sarcoma are treated with the standard dose of nivolumab (240 mg given IV every 3 weeks, Day 1 of every 21-day Cycle). ABI-009 will be given IV on Days 8 and 15 of each cycle starting on Cycle 2 following the 2nd nivolumab dose. Phase 1 portion is a dose-finding study using the 3+3 design. The starting dose of ABI-009 is 56 mg/m2, and sequentially escalating doses are 75 and 100 mg/m2. The primary endpoint is to identify the maximum-tolerated dose (MTD) of ABI-009 + nivolumab, secondary endpoints include disease control rate, progression-free survival (PFS), and overall survival (OS). Exploratory endpoints include correlation of PFS and OS with PD-L1 and other biomarkers. The Phase 2 part of study will enroll 31 additional patients to further assess efficacy and safety at the MTD. Results: 9 patients were treated in Phase 1 (n = 3 each dose level); 5/9 patients had OS, 3/9 CS, and 1 had Ewing sarcoma. No dose-limiting toxicities (DLTs) were observed, the MTD was not reached, and 100 mg/m2 ABI-009 was designated as the recommended phase 2 dose. Safety analysis: At Dose 1: Grade 3 treatment-related adverse events (TRAEs) included hyper dyslipidemia (n = 1), and hyperglycemia (n = 1). At Dose 2: Grade 3 TRAEs included increased ALT (n = 1). At Dose 3: Grade 3 TRAEs included hypophosphatemia (n = 1). Seven of 9 patients have discontinued treatment: 5 patients due to PD, 2 with SD opted to stop treatment due to drug-related Grade 2 AEs (pruritus, acneiform rash, and 2 with SD are still on therapy at Dose 3. The median PFS at dose level 3 has not yet been reached. Conclusions: The MTD was not reached and Dose 3 (100 mg/m2) has been designated as the phase 2 dose of ABI- 009, combinable with nivolumab. Enrollment to phase 2 is ongoing. Clinical trial information: NCT03190174.

Phase 1 Trial of Sorafenib and Everolimus In Patients with Lymphoma or Multiple Myeloma.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2802-2802 ◽  
Author(s):  
Shaji Kumar ◽  
Luis F Porrata ◽  
Stephen M. Ansell ◽  
Joseph P Colgan ◽  
Betsy LaPlant ◽  
...  
Keyword(s):  
Disease Progression ◽  
Dose Level ◽  
Research Funding ◽  
Phase 1 ◽  
Hematologic Toxicity ◽  
Phase 2 ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 2802 Background: Redundancy of pro-survival signaling pathways promotes survival and drug resistance in lymphoid and plasma cell malignancies. In particular, the PI3K-Akt and the MEK-ERK pathways have been shown to play an important role in the proliferation and survival of these malignant cells induced by various cytokines in the tumor microenvironment. Sorafenib, a Raf kinase and VEGF receptor inhibitor, and everolimus, an mTOR inhibitor, have synergistic cytotoxicity in myeloma and lymphoma cells due to inhibition of multiple signaling pathways. Methods: We designed a Phase 1/2 clinical trial to identify the maximum tolerated doses of the two drugs used in combination and the efficacy of the combination. Patients (Pts) with relapsed myeloma or lymphoma were eligible for enrollment. Pts were required to have an absolute neutrophil count ≥1500 × 10(6)/L, a platelet count ≥75,000, and a serum creatinine 21.5 mg/dL. The study utilized the classic 3+3 design. Extensive pharmacokinetic studies were performed to better delineate potential drug interactions. Results: Twenty-six pts were accrued from August 2007 to February 2009. Four pts discontinued sorafenib during cycle 1 for various reasons (2 patient refusal, 1 unrelated medical condition and 1 physician discretion) and were excluded from MTD determination. An additional pt did not have measurable disease and was ineligible, leaving 19 pts with lymphoma (including 6 with Hodgkin lymphoma) and 2 with myeloma for phase I analysis. The pts had a median age of 56 years (range, 22, 69) and were heavily pretreated with a median of 4 prior therapies (range, 1–10). Eighteen (86%) had received a prior stem cell transplant. Four dose limiting toxicities were seen across all dose levels (Table). These included grade 3 vomiting (level 1), grade 4 thrombocytopenia (level 2 and 3, one each) and grade 2 hand and foot rash leading to treatment delay (level 3). Overall, 13 pts experienced a grade 3 or 4 hematologic toxicity. Grade 3 or 4 anemia, neutropenia, and thrombocytopenia occurred in 19%, 43%, and 38% of pts, respectively. Four pts have experienced a grade 3 non-hematologic toxicity; no grade 4 non-hematologic toxicities were seen. Grade 3 non-hematologic toxicities included hypokalemia, weight loss, vomiting, hand-foot skin reaction, fatigue, and elevated alkaline phosphatase. Dose level 1 (sorafenib 200 mg and everolimus 5 mg daily) was best tolerated and was selected for phase 2 evaluation. The ORR was 33% (7/21;95% CI: 15–57%, Table) with 3 pts at dose level 0 (2 PR, 1 CR), one at level 2 (1 PR) and three at level 3 (2 PR, 1 CR) responding. The responders included 5 pts with Hodgkin's disease and one each with an NK cell and T-cell lymphoma. Pts have received a median of 6 cycles (range: 1–19) of treatment. 16 pts have discontinued treatment due to disease progression (13 pts), non-resolution of cytopenias (1 pt), physician discretion (1 pt), and death on study due to lymphoma (1 pt). Disease progression has been seen in 16 pts; 9 pts have died. Median follow-up for pts still alive is 18.7 months (range: 11.5–29.4). 6 pts died from disease progression, one each due to sepsis unlikely related to treatment, cholecystitis, and unknown causes. Sorafenib is metabolized by the cytochrome P450 CYP3A enzyme and RAD-001 mainly by the CYP3A4 system in the liver, hence there is a potential for interactions. The detailed PK analyses performed as part of this trial showed a decrease in the RAD001 levels following initiation of sorafenib on day 8 of cycle 1 (Figure). Conclusion: The combination of sorafenib and everolimus is safe at a recommended phase 2 dose of sorafenib 200 mg and everolimus 5 mg daily. There is no significant drug interaction seen. Activity has been observed, especially in the setting of Hodgkins Disease. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Off Label Use: Lenalidomide for treatment of newly diagnosed myeloma. Witzig:Novartis and Celgene: Patents & Royalties, Research Funding, Served on advisory boards with Novartis and Celgene – both uncompensated with compensation to Mayo Clinic.

Phase 1/2 Study of SB1518, a Novel JAK2/FLT3 Inhibitor, In the Treatment of Primary Myelofibrosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3082-3082 ◽  
Author(s):  
Srdan Verstovsek ◽  
H. Joachim Deeg ◽  
Olatoyosi Odenike ◽  
Joy Zhu ◽  
Hagop Kantarjian ◽  
...  
Keyword(s):  
Abdominal Pain ◽  
Adverse Events ◽  
Disease Progression ◽  
Research Funding ◽  
Response Rate ◽  
Phase 1 ◽  
Study Drug ◽  
Phase 2 ◽  
Associated Symptoms ◽  
Dose Levels

Abstract Abstract 3082 Mutation of Janus Associated Kinase 2 (JAK2) at amino acid 617 and the resulting constitutively active JAK2V617F enzyme has been linked to the pathogenesis of myeloproliferative neoplasms (MPN). SB1518 is a potent ATP-competitive inhibitor of both JAK2 (IC50 = 23 nM) and its JAK2V617F mutant (IC50 = 19 nM) that is selective for JAK2 inhibition compared to JAK1 and JAK3 (58 and 24 fold, respectively). Flt3 inhibition (IC50 = 22nM) is also observed. In the phase 1 portion of this study, target inhibition was evaluated by assessment of the activation state of JAK-STAT pathways as measured by phosphorylation of the STAT3, STAT5 and JAK proteins in PBMCs and whole blood. Inhibition of STAT3 and STAT5 phosphorylation was observed at all dose levels of SB1518 from 100–600 mg daily, and the steady state plasma concentrations at all dose levels were well in excess of the IC50 for the target enzymes JAK2 and FLT3. 400 mg orally daily was selected as the recommended Phase 2 dose based on the response rate (reduction in splenomegaly) and safety and tolerability with long-term administration. Objectives of the Phase 2 portion of the study are to determine the spleen reduction response rate, the duration of spleen response and assess the safety and tolerability of 400 mg SB1518 when administered orally once daily continuously in 28-day cycles. Thirty-three patients with PMF have been enrolled and 32 are evaluable for safety. All patients entered the study with splenomegaly: median span below the left costal margin was 18cm. All had been previously treated: median number of prior systemic therapies was 1. The most common related adverse events have been diarrhea 81% (6% G3), nausea 41% (all G1,2), vomiting 22% (all G1,2), fatigue 9% (all G1,2) and abdominal pain, extremity pain and insomnia 6% (all G1,2) and rash 6% (3% G3). Neutropenia and thrombocytopenia were uncommon (no G3/4 events). Eighteen patients experienced adverse events requiring either study drug interruption and/or dose reduction, the majority reported GI symptoms, in particular diarrhea, as a contributing factor. Three deaths have been reported, two due to disease progression and one due to hemorrhage, none were related to study drug. To date, 23 patients (69.9%) remain on study drug; the median duration on study drug is 3.7 months (range 0.4–4.6 months). Ten patients have discontinued study drug, 1 due to AE, 2 withdrew consent, 1 for disease progression, 5 for lack of response and 1 due to death. 25 patients have completed 12 weeks on study, 17/25 patients were evaluable for response at 12 weeks by MRI. Thirty patients have had response evaluated by physical examination. Significant reductions in spleen size have been observed by both MRI and physical exam. Twelve and 24 week spleen reduction data will be presented for all patients. Bone pain, night sweats, pruritus, fatigue and abdominal pain are being evaluated monthly and a trend for reduction in MF-associated symptoms within the first 12 weeks of treatment has been observed. SB1518 shows promising clinical efficacy with reductions in both splenomegaly and MF-associated symptoms in patients with symptomatic MF and baseline splenomegaly. SB1518 has been well tolerated at the Phase 2 dose of 400mg daily in patients with CIMF. Disclosures: Verstovsek: Incyte Corporation: Research Funding. Odenike:Genzyme Corporation: Research Funding. Zhu:S*BIO: Employment. Kantarjian:Genzyme Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Thomas:Novartis: Honoraria; Bristol-Meyer-Squibb: Honoraria; Pfizer:; Amgen: Research Funding.

Results Of a Phase 1 Study Of Quizartinib (AC220, ASP2689) In Combination With Induction and Consolidation Chemotherapy In Younger Patients With Newly Diagnosed Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 623-623 ◽  
Author(s):  
Jessica K Altman ◽  
James M. Foran ◽  
Keith W. Pratz ◽  
Denise Trone ◽  
Guy Gammon ◽  
...  
Keyword(s):  
Dose Level ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Phase 1 ◽  
Newly Diagnosed ◽  
Consolidation Chemotherapy ◽  
Phase 1 Study ◽  
Level 1 ◽  
Grade 3 ◽  
Dose Levels

Abstract FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) in acute myeloid leukemia (AML) are associated with early relapse after standard chemotherapy and poor survival. Quizartinib (AC220) is an oral FLT3 receptor tyrosine kinase inhibitor that has shown the highest level of single agent activity seen with a FLT3 targeted agent in FLT3+ relapsed AML to date. This Phase 1 dose escalation study is the first study to report data with quizartinib in combination with standard induction and consolidation chemotherapy in patients aged 18-60 years with newly diagnosed AML, regardless of FLT3-ITD status. The dose escalation was conducted using a modified 3+3 design, where 6 pts were enrolled at each dose level. The pts were given cytarabine 200 mg/m2 x 7 days and daunorubicin 60 mg/m2 x 3 days (7+3) for induction and high dose cytarabine 3 g/m2(HiDAC) q12hours on days 1, 3, and 5 for consolidation. Quizartinib was administered daily for either 7 or 14 days, starting at Day 4 of induction and/or consolidation chemotherapy. Patients were allowed to proceed directly to a stem cell transplant after achieving a response or receive further quizartinib as maintenance therapy after consolidation if they were not transplant eligible. Three dose levels were tested; dose level 1 (DL1) at 60 mg for 7 days, dose level 2 (DL2) 60 mg for 14 days, and dose level -1 (DL-1), 40 mg for 14 days. Through May 31, 2013 18 pts were enrolled in the study, and the safety information at all 3 dose levels are presented. The median age of pts was 43 years (range 22 to 60). Of the 18 patients, 16 had the FLT-ITD mutation. At DL1, one of the 6 patients had a DLT (grade 3 hyponatremia). At DL2, two of the 6 patients had a DLT (grade 3 QTc prolongation and grade 4 pericarditis) which exceeded the pre-specified criteria so DL-1 was then explored. At DL-1, one of the 6 patients had a DLT (grade 3 constrictive pericarditis). The most common (20%) treatment-related adverse events (AEs) were nausea (42%), diarrhea (32%), anemia (26%), febrile neutropenia (26%), neutropenia (21%), fatigue (21%), pyrexia (21%) and thrombocytopenia (21%). The most common (10%) Grade 3 or 4 treatment-related AEs were febrile neutropenia (26%), thrombocytopenia (21%) anemia (21%)), neutropenia (21%), leucopenia (16%), and nausea (11%). The data from this Phase 1 study demonstrates for the first time that quizartinib can be safely administered with induction and/or consolidation chemotherapy in newly diagnosed younger patients with AML. The MTD was identified as 40 mg for 14 days or 60 mg for 7 days. The efficacy results from this Phase 1 study will be available at the time of presentation. Based on these findings, multiple Phase 3 studies in newly diagnosed AML patients are planned. Disclosures: Altman: Novartis: Consultancy; Araid: Consultancy; BMS: Consultancy; Teva: Consultancy; Astellas: Consultancy. Foran:Astellas: Research Funding. Trone:Ambit: Employment. Gammon:Ambit: Employment. Cortes:Ambit: Research Funding.

scholarly journals A Phase 1 Study of Tasquinimod in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 17-18
Author(s):  
Dan T. Vogl ◽  
Yulia Nefedova ◽  
E. Paul Wileyto ◽  
Harjeet Sembhi ◽  
Inna Strakovsky ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Optimal Schedule ◽  
Study Endpoint ◽  
Expansion Cohort

Background Multiple myeloma (MM) is a hematologic malignancy resulting from clonal proliferation of plasma cells in the bone marrow (BM). The BM tumor microenvironment confers therapeutic resistance through survival and growth signals to myeloma cells and suppression of anti-tumor immune responses. A population of myeloid-derived suppressor cells (MDSCs), abundantly producing the pro-inflammatory S100A9 protein, promotes myeloma progression. Tasquinimod (TASQ) is an investigational drug that targets MDSCs via the S100A9 protein. In pre-clinical models of MM, TASQ has significant anti-tumor effects as a single agent and in combination with bortezomib, a proteasome inhibitor (PI) and lenalidomide, an immunomodulator (IMiD) (Lin C, et al. 25th Annual Meeting of European Hematology Association June 11-21 2020: EP896). TASQ has previously been studied as a novel, once-daily oral anti-cancer agent, including in a phase-3 randomized trial in patients (pts) with metastatic prostate cancer that showed improvement in radiographic progression-free survival (Sternberg C, et al. JCO 2016; 34(22): 2636-43). The side effect profile of TASQ is well-characterized based on this previous experience. We therefore designed a phase 1 trial (NCT04405167) to establish the maximum tolerated dose (MTD) and optimal schedule for TASQ in MM and then investigate the MTD of TASQ in combination with a standard oral myeloma regimen of ixazomib, lenalidomide, and dexamethasone (IRd). For both single agent TASQ and the combination of TASQ with IRd, exploratory expansion cohorts will be enrolled to preliminarily characterize the antimyeloma activity of each regimen. Study Design Enrolled pts must have MM relapsed or refractory after at least one prior line of anti-MM therapy. Other key inclusion criteria include measurable disease and Eastern Cooperative Oncology Group performance status ≤2. Key exclusion criteria include failure to have fully recovered from clinically significant adverse effects of prior chemotherapy; active graft versus host disease; treatment with cytotoxic chemotherapy within 3 weeks prior to initiation of study treatment; treatment with PIs, IMiDs, or monoclonal antibodies within 2 wks, experimental therapy or plasmapheresis within 4 wks, or systemic corticosteroids or radiotherapy within 7 days; known central nervous system involvement by myeloma; or a diagnosis of smoldering MM or POEMS syndrome, active plasma cell leukemia, symptomatic primary amyloidosis, or myelodysplastic or myeloproliferative syndrome. Single agent TASQ and the combination of TASQ with IRd will be investigated in two parts. Part A will start with dose-escalation of single agent TASQ using a standard 3+3 design, with 3 to 6 pts evaluable for dose-limiting toxicity at each dose-level (see table). In the subsequent expansion cohort, additional pts will enroll at the MTD/optimal schedule, so that 12 pts total evaluable for response will have received the MTD/optimal schedule of single agent TASQ. Part B combines TASQ with standard-dose IRd: 28-day cycles of ixazomib 4 mg on days 1, 8, and 15, lenalidomide 25 mg on days 1-21, and dexamethasone 40 mg on days 1, 8, 15, and 22. The part B dose-escalation starts at the lower of either dose-level 1 or one dose-level below the single agent MTD. Additional pts with disease refractory to their most recent PI/IMiD combination will enroll into a part B expansion cohort, so that 12 pts total who are both evaluable for response and PI/IMiD refractory will have received the MTD/optimal schedule of TASQ in combination with IRd. Treatment will continue until unacceptable toxicity or myeloma progression. The primary study endpoint is the MTD of TASQ as single agent and in combination with IRd. Key secondary endpoints include toxicity (treatment-emergent grade 3/4 adverse events using the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 5), preliminary antimyeloma activity (using the response criteria of the International Myeloma Working Group), changes in the BM microenvironment, and systemic TASQ exposure during therapy with single-agent TASQ and during therapy with TASQ in combination with IRd. These results will determine whether TASQ, alone or combined with standard anti-MM therapy, represents a promising novel treatment strategy in MM. Table 1 Disclosures Vogl: Active Biotech: Consultancy, Research Funding; Janssen: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Oncopeptides: Consultancy; MorphoSys: Consultancy. Nefedova:Active Biotech: Consultancy, Research Funding. Bondesson:Active Biotech: Current Employment. Eriksson:Active Biotech: Current Employment. Tuvesson:Active Biotech: Current Employment. OffLabel Disclosure: Tasquinimod for multiple myeloma

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