Combined Bendamustine, Prednisolone and Lenalidomide (RBP) In Refractory or Relapsed Multiple Myeloma. First Results of a Phase I Clinical Trial

Abstract Abstract 1971 Introduction: While the role of lenalidomide monotherapy in the treatment of relapsed/refractory patients with multiple myeloma (MM) is established, combination therapies with Lenalinomide are still under investigation. Bendamustine is a bi-functional alkylating agent with a purine-like benzimidazole ring effective in combination with steroids, thalidomide and bortezomib for the treatment of patients with MM. In the current trial, combination therapy of bendamustine, lenalinomide and prednisolone (RBP) was tested for feasibility and safety in patients with relapsed or refractory MM. Patients and Methods: This is a phase I trial examining dosing of lenalidomide in combination with bendamustine and prednisolone. The first cohort of patients received a starting dose of 10mg/d d1-21 lenalidomide, 60mg/m2/d d1-2 bendamustine and 100mg/d d1-4 prednisolone. Escalation steps in the next cohorts included 15, 20 and 25mg of lenalidomide followed by an escalation step of 75 mg/m2 bendamustine. Three patients were enrolled at each dose level and the first two cycles were evaluated for maximum tolerable dose. Patients received RBP in 4-week cycles for a maximum of 8 cycles in order to evaluate efficacy. Patients with stable or responding disease following 8 cycles of RBP received single-agent oral lenalidomide 10 mg once daily on days 1–21 of each 28-day cycle as maintenance. Results: : Nine patients (3 at each dose level of 10 mg, 15 mg or 20 mg lenalidomide) have been enrolled to date and 9 patients have completed at least 2 cycles. Response was assessed using modified EBMT criteria to include near complete remission (nCR) and very good partial remission (VGPR). 8 of 9 patients responded after at least 2 cycles with 2 VGPR, 4 PR, 1 MR and 1 stable disease. One patient experienced progressive disease. None of the 9 patients developed dose-limiting hematoxicity as defined by an ANC < 1,0 × 109/l with fever for > 3 days or an ANC <0,5 × 109/l for > 7 days or platelet count < 25 × 109/l for > 3 days. Neutropenia was reported in 4 patients (CTC grade ≥ 3) but no thrombocytopenia (CTC grade ≥ 3) was observed. No grade 3 or 4 non hematological toxicity was encountered and no dose modification was required. Conclusions: RBP with a dose of 20 mg lenalidomide d 1–21 and 60 mg/m2 bendamustine d 1–2 is well tolerated in patients with relapsed or refractory MM. Maximum tolerable dose was not reached. Further dose increase according to the protocol is in progress. Disclosures: Niederwieser: Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau.

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EPCT-17. A PHASE I AND SURGICAL STUDY OF RIBOCICLIB AND EVEROLIMUS IN CHILDREN WITH RECURRENT OR REFRACTORY MALIGNANT BRAIN TUMORS: PEDIATRIC BRAIN TUMOR CONSORTIUM INTERIM REPORT

Neuro-Oncology ◽

10.1093/neuonc/noaa222.139 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii307-iii307

Author(s):

Mariko DeWire ◽

Christine Fuller ◽

Olivia Campagne ◽

Tong Lin ◽

Haitao Pan ◽

...

Keyword(s):

Brain Tumors ◽

Phase I ◽

Dose Level ◽

Phase I Study ◽

Single Agent ◽

Pediatric Brain Tumor ◽

Pi3k Pathway ◽

Neurosurgical Procedures ◽

Common Grade ◽

Grade 3

Abstract Genomic aberrations in the cell cycle and PI3K pathway are commonly observed in recurrent childhood brain tumors. Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dosage (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus was determined in the Phase I study and ribociclib concentrations were characterized in plasma and tumor in children undergoing neurosurgical procedures. Following resection, eligible patients were enrolled in the Phase I study according to a rolling 6 design and received ribociclib and everolimus once daily for 21 days and 28 days, respectively. Patients undergoing surgery received ribociclib at the pediatric RP2D (350 mg/m2/day) for 7–10 days pre-operatively. Pharmacokinetic samples were collected on both cohorts and analyzed in nine patients on phase I study. Sixteen eligible patients enrolled on phase I study (median age 10.3 years; range: 3.9–20.4) and 5 patients were enrolled on the surgical cohort (median age 11.4 years; range: 7.2–17.1). Six patients enrolled at dose level 1 without dose limiting toxicities (DLT). Two of the three patients at dose level 2 experienced DLT (grade 3 hypertension and grade 4 ALT). The most common grade 3/4 toxicities were lymphopenia, neutropenia, and leucopenia. Everolimus concentrations following administration of everolimus alone were lower than those following drug combination, suggesting an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus in recurrent CNS tumors is 120 mg/m2 and 1.2 mg/ m2 daily for 21 days and 28 days, respectively.

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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.

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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.

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

Blood ◽

10.1182/blood.v112.11.1723.1723 ◽

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.

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

Blood ◽

10.1182/blood.v114.22.1874.1874 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1874-1874 ◽

Cited By ~ 4

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.

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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 ◽

10.1182/blood.v120.21.2965.2965 ◽

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.

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A phase I study of S-1 administration and a 24-h infusion of cisplatin plus paclitaxel in patients with advanced gastric cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.4074 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 4074-4074

Author(s):

H. Iwase ◽

M. Shimada ◽

T. Tsuzuki ◽

M. Okeya ◽

K. Kobayashi ◽

...

Keyword(s):

Gastric Cancer ◽

Antitumor Activity ◽

Advanced Gastric Cancer ◽

Dose Level ◽

Combination Chemotherapy ◽

Single Agent ◽

Fixed Dose ◽

Hematological Toxicity ◽

Level 3 ◽

Grade 3

4074 Background: S-1 may have a major role in the treatment of gastric cancer as single agent or as a component of combination chemotherapy in Japan. We previously reported a multicentric phase II study of S-1 combined with a 24-h infusion of cisplatin in patients with advanced gastric cancer. This combination was active, safe and had the possibility of being combined with other anticancer drug. Combination chemotherapy with S-1 and cisplatin plus paclitaxel for advanced gastric cancer might yield a stronger antitumor effect. The objective of this study was to determine the dose-limiting toxicity (DLT), the maximum tolerated dose (MTD), the recommended dose (RD), and the preliminary antitumor activity of S-1 and cisplatin plus paclitaxel for advanced gastric cancer. Methods: Paclitaxel was administered on day 1. A fixed dose of S-1 (70 mg/m2/day) was orally administered for 14 consecutive days from day 1, and a 24-h infusion of a fixed dose of cisplatin (60 mg/m2) was administered on day 14 of every 28-day cycle. Four dose escalation levels of paclitaxcel were studied (120, 140, 160, and 180 mg/m2). The DLT was defined as any of the following: grade 3 neutropenia lasting more than 5 days, grade 4 hematological toxicity, grade 3 non-hematological toxicity, or treatment delay of greater than 2 weeks as a result of toxicity. Results: Twenty patients were enrolled. Hematological and non- hematological toxicity of over grade 2 was not observed at dose level 1 and 2. Three patients started at dose level 3. One developed grade 3 neutropenia for 5 days following by grade 2 neutropenia lasted more than 10 days. Five more patients were added at this level. The treatment was delayed over 2 weeks in 1 out of 8 patients. Three patients started at dose level 4. One developed grade 3 neutropenia and needed longer than 14 days to recover. Three patients added this level. In total, at dose level 4 the treatment was delayed over 2 weeks in 3 out of 6 patients as a result of neutropenia. We considered level 4 is the MTD and the RD of paclitaxcel was 160 mg/m2 (dose level 3). The overall response rate was 75%. Conclusions: Triple combination chemotherapy consisting of S-1, cisplatin, and paclitaxel showed a tolerable dose of adverse reactions and favorable antitumor activity for gastric cancer. No significant financial relationships to disclose.

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Pooled analysis of phase I dose-escalation and dose cohort expansion studies of IMP4297, a novel PARP inhibitor, in Chinese and Australian patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.3059 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 3059-3059 ◽

Cited By ~ 1

Author(s):

Junning Cao ◽

Pin Zhang ◽

Paul L. de Souza ◽

Bo Gao ◽

Mark Voskoboynik ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Level ◽

Dose Escalation ◽

Single Agent ◽

Response To Treatment ◽

Clinical Activity ◽

Dose Cohort ◽

Phase Ii Studies ◽

Grade 3

3059 Background: Poly (ADP-ribose) polymerase (PARP) enzymes play critical roles in DNA damage detection and repair. IMP4297 is a novel, potent PARP1/2 inhibitor (IC50 6.27nM/1.57nM) and has demonstrated to be 20-fold more potent than Olaparib in anticancer animal models. Two phase I studies were performed to evaluate and characterize the tolerability and safety, pharmacokinetics, and antitumor activity of single agent IMP4297 in Chinese and Australian patients with advanced ovarian, breast, prostate and other solid tumors. Methods: Dose escalation used a 3+3 design with a modified Fibonacci escalation. Dose cohort expansion was planned after efficacy was observed at the lowest dose level. Patients received IMP4297 monotherapy orally once a day until disease progression or unacceptable toxicity. Results: As of Jan 12, 2019, 56 patients, including 23 BRCA mutation carriers (BRCA+), had been enrolled at 2-100 mg dose level. No DLT was observed. In these two studies, the most frequent treatment-related adverse events (TRAEs) were leukopenia (20%), followed by anemia (18%), nausea (18%) and thrombocytopenia (14%). The majority of TRAEs were grade 1 or 2. Grade 3 TRAEs occurred in five patients (anemia, n=2; vomiting, n=1; thrombocytopenia, n=1; elevated AST, n=1). Only one patient had a dose reduction due to grade 3 thrombocytopenia. No serious TRAEs were observed. In 15 BRCA+ patients who had measurable lesions, the ORR was 33% and the DCR was 80%. There were 4 BRCA+, platinum-sensitive ovarian cancer patients with an ORR of 75% and a DCR of 100%. One patient with somatic BRCA mutated urothelial carcinoma showed a 76% decrease in tumor size. Conclusions: IMP4297 has been well-tolerated with significant anti-tumor activity. The 100 mg daily dose was selected as the RP2D based on safety, pharmacokinetics and clinical activity, and will be further characterized in dose expansion and phase II studies. Tumor response to treatment (RECIST 1.1) in patients with measurable lesions. Clinical trial information: NCT03508011 and NCT03507543. [Table: see text]

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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

Blood ◽

10.1182/blood-2019-129683 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5591-5591

Author(s):

Hong-Hui Huang ◽

Jian Hou ◽

Yang-Ming Zhang ◽

Yu-Bo Zhou ◽

Li Jia ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Hdac Inhibitor ◽

Phase 1 ◽

Single Agent ◽

Human Study ◽

Weekly Schedule ◽

Phase 1 Study ◽

Expansion Phase ◽

Grade 3

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.

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A Phase I Trial of Ibrutinib Plus Palbociclib in Patients with Previously Treated Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v128.22.150.150 ◽

2016 ◽

Vol 128 (22) ◽

pp. 150-150 ◽

Cited By ~ 7

Author(s):

Peter Martin ◽

Kristie Blum ◽

Nancy L. Bartlett ◽

Steven I. Park ◽

Kami J. Maddocks ◽

...

Keyword(s):

Phase I ◽

Mantle Cell Lymphoma ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

Hematological Toxicity ◽

Mantle Cell ◽

Previously Treated ◽

Grade 3 ◽

Dose Levels

Abstract Background Single-agent ibrutinib confers a response rate of 77%, including a complete response (CR) rate of 19% in patients with previously treated mantle cell lymphoma (MCL); however, with a median progression-free survival (PFS) of 14.6 months and 1-year response duration (RD) rate of 69%, nearly half of all patients experience treatment failure during the first year. We previously demonstrated that prolonged early G1 cell cycle arrest induced by the oral, specific CDK4/6 inhibitor palbociclib can overcome ibrutinib resistance in primary human samples and MCL cell lines with wild-type BTK (Chiron et al. Cancer Discovery 2014). We conducted a phase I trial to evaluate the safety and preliminary activity of palbociclib plus ibrutinib in patients with previously treated mantle cell lymphoma. Methods Adult patients who were ibrutinib and CDK4/6 inhibitor-naïve who had previously treated MCL were eligible to participate. The primary objective was to estimate the maximum tolerated dose of the combination. Consenting patients were enrolled to one of five dose levels, shown in Table 1. Patients were treated in 28 day cycles, with ibrutinib administered daily and palbociclib administered on days 1-21. (Table 1). Patients could continue to receive study treatment until progression, unacceptable toxicity, or withdrawal of consent. Doses were escalated according to a standard phase I 3+3 design. Patients were evaluated for efficacy at the end of cycles 3 and 6, and every 6 cycles thereafter. All CRs, as documented by CT, required confirmation by PET/CT; bone marrow biopsy and endoscopy were also required in patients with known marrow or GI tract involvement, respectively. Additional objectives included pharmacokinetics and evaluation of pretreatment samples for biomarkers of response or resistance. Results From August 2014 to June 2016 a total of 20 patients (15 males, 5 females) were enrolled (DL1 n=3, DL2 n=3, DL3 n=6, DL4 n=3, DL5 n=5). The patients' MIPI risk distribution were 7 low, 7 intermediate, and 6 high. The median number of prior therapies was 1 (range 1-5). Six patients were refractory to their last prior therapy. Three patients experienced dose limiting toxicity: One patient treated at DL3 experienced grade 4 thrombocytopenia lasting more than 7 days, and grade 3 rash was seen in two patients at DL5. Grade 3-4 hematological toxicity included thrombocytopenia (28%), neutropenia (22%), and lymphopenia (17%). Grade 3-4 non-hematological toxicity regardless of attribution included one patient with each of the following: lung infection, ALT/AST increase, encephalitis, hyponatremia, sinus tachycardia, pneumonitis. Grade 1-2 adverse events related to treatment and occurring in at least 2 patients included the following: diarrhea (50%), fatigue (44%), rash (39%), bruising (17%), nausea (17%), fever (11%), dyspepsia (11%), and myalgia (11%). Other than the two patients that experienced grade 3 rash at DL5, no patients have required dose reductions; 6 patients required dose interruptions. Thirteen subjects continue on study therapy. The reasons for stopping treatment were disease progression (n=4), adverse event (elevated liver enzymes, n=1; and prolonged cytopenias, n=1), and allogeneic stem cell transplantation (n=1). Of the 18 patients that have had at least one response evaluation to date, 12 (67%) patients responded to treatment and 8 (44%) achieved a CR. The median time to CR was 3 cycles and no responding patients have progressed on study. With a median follow up of 11 months, the estimated 1-year PFS and RD are 68% and 100%, respectively (Figure 1). Conclusions The mechanism-based combination of ibrutinib plus palbociclib is well tolerated and active. Toxicity is primarily related to myelosuppression of grade 1-2 severity, although grade 3 rash was observed at the highest doses evaluated. In this small group of patients, the combination produced responses at all dose levels, with a CR rate of 44% and a median time to CR of 3 months. No responding patients have progressed to date. These preliminary CR, PFS, and RD rates appear better than those reported in other studies of single-agent ibrutinib although the numbers of patients was very small. A phase II multi-center clinical trial to evaluate time to progression is planned. Biomarker studies to evaluate mechanisms of primary resistance are ongoing. Disclosures Martin: Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Other: travel, accommodations, expenses; Novartis: Consultancy; Acerta: Consultancy; Teva: Research Funding. Ruan:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics, LLC, an AbbVie Company: Research Funding, Speakers Bureau; Janssen: Research Funding.

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