Safety and efficacy of YM155 in diffuse large B-cell lymphoma (DLBCL)

8502 Background: Survivin is a member of the inhibitor of apoptosis proteins (IAPs) family which is responsible for preservation of cell viability and regulation of mitosis in tumor cells. YM155, a survivin suppressant, has exhibited anti-tumor activity in solid tumors and non-Hodgkins lymphoma (NHL), including DLBCL patients enrolled in Phase I and Phase II monotherapy studies. Methods: Two studies enrolled 43 DLBCL patients; a Phase I study enrolled patients with solid tumors and NHL (n=1 relapsing DLBCL and n=1 refractory DLBCL), and a Phase II study enrolled refractory DLBCL patients (n=41). YM155 was administered at 4.8 mg/m2/day (Phase I) and at 5 mg/m2/day (Phase II) as a 168-hour continuous infusion in a 21 day cycle. Patients could continue to receive YM155 until disease progression or unacceptable toxicity. Results: Data are presented for the first 27 patients (Phase I and Phase II) who have completed therapy. Median age was 61 (23–80) years and 63% were male. Three patients (11%) had partial responses (PR) confirmed by independent review using Cheson criteria (N=2; 1999 criteria and N=1; 2007 updated criteria). All responders received 2 prior regimens. Two responders were refractory to their last regimen and one had relapsed approximately 2 years after stem cell transplant (SCT). One patient responded after 2 cycles, completed 5 total cycles and proceeded to SCT (disease-free > 3.7 years post SCT). A second patient responded after 3 cycles, completed 7 total cycles and proceeded to SCT in OCT08. The third patient responded after 12 cycles and received 26 total cycles (1.5 years) before disease progression. The most common (>4%), treatment-related grade 3/4 adverse events included anemia (16.0%) and neutropenia, fatigue, hemoglobin decrease and deep vein thrombosis (8.0% each). Conclusions: YM155 is well tolerated and has modest single-agent, anti-tumor activity in relapsed/refractory DLBCL patients. Because of single-agent activity and preliminary data showing synergism when YM155 is combined with other agents additional clinical studies are being planned. [Table: see text]

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Temsirolimus in Combination with Bendamustine and Rituximab for the Treatment of Relapsed Mantle Cell and Follicular Lymphoma: Report on an Ongoing Phase I/II Trial

Blood ◽

10.1182/blood.v126.23.3930.3930 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3930-3930

Author(s):

Georg Hess ◽

Ulrich Keller ◽

Johannes Atta ◽

Ulrich Bitz ◽

Christian Lerchenmueller ◽

...

Keyword(s):

Phase I ◽

Phase Ii ◽

Research Funding ◽

Single Agent ◽

B Cell Lymphoma ◽

Response Rates ◽

Phase Iii ◽

Mtor Inhibition ◽

Grade 3 ◽

Ongoing Phase

Abstract Background: mTOR inhibition has been shown to be effective in various subtypes of malignant lymphomas. In relapsed MCL a phase III trial could prove superiority of Temsirolimus to standard options. Furthermore, in patients with follicular and diffuse large B-cell lymphoma, promising response rates could be observed (Smith et al, JCO 2010). Whereas combination to single agent Rituximab (R) improved efficacy (Ansell et al, Lancet Oncology 2011), there is limited information of the feasibility and efficacy in combination with chemotherapy. Bendamustine (B) has been shown to be effective in various lymphoma entities and has a beneficial side effect profile (Rummel et al, JCO, 2005). In the phase I of this trial, we have established that 50mg of Temsirolimus given 3 times weekly in a four week cycle could be safely added to BR (Hess, Leukemia, 2015). Here we report for the first time combined results of phase I and II of this trial. Methods: this is a multicenter, national, prospective trial. Inclusion criteria: patients were eligible if they had histologically proven FL or MCL, 1-3 prior treatment lines, no curative option available, no refractoriness to Bendamustine, measurable disease, ECOG < 3, sufficient bone marrow reserve, no severe concomitant diseases and given informed consent. Treatment consisted of Bendamustine 90mg/m² day 1-2, Rituximab 375mg/m² day 1 and Temsirolimus 50 mg day 2, 8, 15 of a 28d cycle. A total of 4 cycles was planned with interim staging after 2 cycles. Results: Overall 34 patients (pts) have been included until now (15 pts phase I, 19 pts phase II). Concerning clinical characteristics, median age was 71 years, with 25 MCL and 9FL, and a median number of 2 pretreatments (1-3). Overall the treatment was well tolerated, and toxicity was predominantly hematologic. In 118 evaluable cycles of chemotherapy the following hematologic grade 3 / 4 toxicities were noted: leukopenia (11 pts, 32%), neutropenia (8 pts, 24%), and thrombocytopenia (7 pts, 21%). Non-hematologic grade 3 / 4 observed in at least two patients were angioedema and decrease in blood potassium, infection, metabolic (4 events). AE's of special interest: pulmonary: rate of cough (4; 12%) and pneumonitis (1; 3%); gastrointestinal: diarrhea (6; 18%), nausea (13, 38%); general: fatigue (16; 47%), mucositis (13, 38%); bleeding: epistaxis (4; 12%), which all were predominantly grade 1 or 2. Response: currently, best responses were 8 CR (31%), 16 PR (62%) and 2 SD (8%) in 26 patients evaluable so far. Updated results will be presented at the meeting. Overall responses were 94% in MCL (7 CR, 10 PR, 1 SD) and 88% in FL (1 CR, 6 PR, 1 SD). After a median follow up of 13 months (mean: 21 months) median PFS is 18.6 months for the entire cohort, with 22 months for MCL and not reached in FL. Summary: In this ongoing phase II trial 50mg Temsirolimus (day 1,8,15) in combination with Bendamustine and Rituximab was well tolerated and feasible. A moderate dose of Temsirolimus to standard chemotherapy might be the optimal way to achieve the maximum efficacy with mTOR inhibitors; in fact excellent response rates suggest an additive effect of mTOR inhibition to BR. Even after the BTK inhibitor Ibrutinib has entered the clinical arena of MCL, this combined treatment represents a valuable additional option especially for patients with relapsed MCL Disclosures Hess: Pfizer, Janssen, Roche, Mundipharma: Honoraria, Research Funding; Janssen, Roche, , Celgene, Novartis: Consultancy. Keller:Roche: Consultancy, Honoraria; Pfizer: Consultancy. Witzens-Harig:Roche: Honoraria; Pfizer: Honoraria, Research Funding.

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A phase I study of bevacizumab (BV) plus ABT-510 in patients with advanced solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.3541 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 3541-3541 ◽

Cited By ~ 1

Author(s):

H. E. Uronis ◽

J. Bendell ◽

G. Blobe ◽

M. Morse ◽

D. Geier ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Phase Ii ◽

Single Agent ◽

Hematological Toxicity ◽

Synthetic Analog ◽

Advanced Solid Tumors ◽

Increased Risk ◽

Grade 3 ◽

Recommended Phase Ii Dose

3541 Background: BV is a potent inhibitor of vascular endothelial growth factor (VEGF) with broad clinical activity both alone and in combination. ABT-510 is a 9 amino acid synthetic analog of the N-terminal region of thrombospondin (TSP-1), an endogenous inhibitor of angiogenesis. ABT-510 exhibits anti-angiogenic effects in preclinical models and has been well-tolerated as a single agent in previous Phase I & 2 studies. As a combination anti-angiogenesis therapy, we evaluated BV + ABT-510 in a phase I biomarker study. Methods: In cohorts of 3–6 patients, BV and ABT-510 were evaluated. BV was dosed in mg/kg IV q2weeks and ABT-510 was given daily in mg SC BID; cycle length was 28 days. Dose levels were as follows: (1) BV 5/ ABT-510 50; (2) BV 10/ ABT-510 50; (3) BV 10/ ABT-510 100. At the recommended phase II dose, 20 patients are being enrolled for detailed biomarker studies. DLT was defined as any hematological toxicity = grade 4 or grade = 3 non- hematological event in Cycle 1 related to treatment, with the exception of grade 3 hypertension adequately controlled by medication. Eligible patients had advanced solid tumors, adequate organ and marrow function, and no co-morbidities suggesting increased risk for class-related toxicities. Dermal wound angiogenesis assays were analyzed for visualization as well as phospho-VEGFR2, TGFβ, phospho-AKT, and thrombospondin-1 and -2, both pre- and on-treatment. Plasma was assayed for multiple angiogenic factors. Results: 22 patients have been enrolled; 17 are currently evaluable for toxicity and 14 for efficacy. No DLT were seen in any cohort. Possible treatment related adverse events occurring in later cycles included: gr3 GI bleed (n=1) and gr3 headache (n=1). 7 patients had stable disease as best response (range 8- 64+ weeks); 2 remain on therapy, one at 64+ weeks and one at 24+ weeks. Conclusions: BV + ABT-510 is well-tolerated and has hints of activity in refractory tumors. The recommended phase II dose is BV 10mg/kg IV q14d and ABT-510 100mg SC BID. Updated clinical and biomarker data will be presented. No significant financial relationships to disclose.

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Phase I Results of Combination Gemcitabine and Bortezomib (Velcade®) for Relapsed/Refractory Nodal T-Cell Non-Hodgkin Lymphoma (T-NHL) and Aggressive B-Cell NHL (B-NHL).

Blood ◽

10.1182/blood.v112.11.2005.2005 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2005-2005 ◽

Cited By ~ 6

Author(s):

Andrew M. Evens ◽

Leo I. Gordon ◽

David Patton ◽

Steven T. Rosen ◽

Jane N. Winter ◽

...

Keyword(s):

Phase I ◽

Phase Ii ◽

Phase I Study ◽

Single Agent ◽

Dose Intensity ◽

Clinical Activity ◽

Repeated Treatment ◽

Treatment Schedule ◽

Cell Transplant ◽

Grade 3

Abstract NF-κB is deregulated in several lymphoma subtypes, including aggressive B-NHL and T-NHL. The proteasome inhibitor, bortezomib, has the capacity to reverse some of the downstream consequences of NF-κB, but has only modest single-agent activity in aggressive NHL. Gemcitabine has a favorable toxicity profile and non-cross resistant mechanism of action with agents typically used in the first-line setting. Tumor cell lines and murine xenograft models demonstrate synergy between these two agents. Based on this data and the continued unmet clinical need for patients with relapsed/refractory aggressive NHL either ineligible for or relapsed after stem cell transplant (SCT), we conducted a phase I trial of the combination to determine a dosing regimen for phase II investigation. The phase I design was a 3+3 dose escalation of bortezomib (1.3 mg/m2 and 1.6 mg/m2, day (D) 1 and D8) with static gemcitabine dosing (800 mg/m2 D1 and D8) given on 21-day cycles. Following completion of bortezomib escalation, the phase II portion of the study was initiated. We report here the phase I study including toxicity and preliminary outcomes. 18 patients have enrolled, of whom 15 are evaluable for safety and preliminary efficacy. There were 8 women and 7 men, median age was 56 years (range 37–85 years), median prior therapies were 3 (range 2–5), and 67% had failed prior SCT. Histologies included diffuse large B-NHL (n=5) and T-NHL (1 hepatosplenic, 1 anaplastic, 2 angioimmunoblastic, 6 peripheral NOS). 11 pts accrued to the phase I portion. No dose limiting toxicity (DLT) was seen at bortezomib 1.3 mg/m2 (n=3 patients); 8 phase were tested at the next phase I dose level of bortezomib 1.6 mg/m2 since 2 patients experienced non-hematologic DLT (grade 3 hypertension and grade 3 liver function tests). The study continued to the phase II portion using bortezomib 1.6 mg/m2, in which 4 patients accrued. On planned analysis of the first 15 patients enrolled, it was noted that despite not meeting criteria for DLT, 10/15 patients experienced grade 3/4 neutropenia and/or thrombocytopenia resulting in repeated treatment delay(s). The median number of cycles delivered for all patients was 1 (range 1–3), while the median normalized dose-intensity was only 61%. Thus the trial was amended to institute a modified treatment schedule to administer gemcitabine and bortezomib on D1 and D15 on a 28-day schedule. Pre-planned analysis of the first 15 pts showed clinical activity/response allowing continuation of accrual onto the phase II portion (two partial remissions in T-NHL). In summary, our phase I study defined the safety/toxicity panel of combined bortezomib and gemcitabine dosing for patients with relapsed aggressive NHL. A planned analysis of the first 15 patients showed preliminary activity in heavily pre-treated patients allowing continuation to the 2nd stage, although repeated hematologic toxicities were seen leading to low dose intensity. Of note, data presented at ASCO 2008 (Luu et al. abstract #2563) studied the combination of bortezomib (D1, D4, D8, and D11) and gemcitabine (1,250 mg/m2 D1 and D8) in relapsed/ refractory advanced-stage solid tumors. The maximum tolerated dose of bortezomib there was 1.0 mg/m2 with gemcitabine. Furthermore, significant hematotoxicity was seen in that trial (grade 3/4 toxicity: 62% thrombocytopenia, 34% neutropenia, 17% anemia; with median of 2 cycles delivered). Accrual here continues to the phase II trial using a modified treatment schedule (gemcitabine 800 mg/m2 and bortezomib 1.6 mg/m2 both D1 and D15 on a 28-day schedule) in order allow more consistent delivery of the intended therapy.

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A Phase II Trial Of Epigenetic Modulators Vorinostat In Combination With Azacitidine (azaC) In Patients With The Myelodysplastic Syndrome (MDS): Initial Results Of Study 6898 Of The New York Cancer Consortium

Blood ◽

10.1182/blood.v122.21.386.386 ◽

2013 ◽

Vol 122 (21) ◽

pp. 386-386 ◽

Cited By ~ 7

Author(s):

Lewis R. Silverman ◽

Amit Verma ◽

Rosalie Odchimar-Reissig ◽

Eric J. Feldman ◽

Shyamala C. Navada ◽

...

Keyword(s):

High Risk ◽

Myelodysplastic Syndrome ◽

Phase I ◽

Phase Ii ◽

Single Agent ◽

Response Duration ◽

Initial Response ◽

Cell Transplant ◽

Grade 3

Abstract Background The hypomethylating agent (HMA) azaC reverses epigenetic silencing and is the first agent demonstrated to improve survival in patients with higher-risk MDS (Silverman et al JCO 2002, Fenaux et al Lancet Oncology 2009). Time to initial response with single agent azaC, is 3 to 4 cycles, the CR rate ranges from 7 to 17% and overall response is 45-50%. Vorinostat, a histone deacetylase inhibitor (HDACI) which inhibits class I and II HDAC, has demonstrated single agent activity in patients with MDS with responses of 20% (Garcia-Manero Blood 2006). In vitro the 2 agents are synergistic in reactivating epigenetically silenced genes. The effect is sequence-dependent requiring exposure to the HMA first followed by the HDAC. We conducted a phase I pilot study of escalating and de-escalating doses of the 2 drugs in combination in 8 cohorts and demonstrated broad activity with responses ranging up to 80% across all of the cohorts tested (Blood 2008). Purpose To determine the response rate of patients treated with the combination of vorinostat and azacitidine at the doses established as safe and effective in Phase I in an expanded cohort of patients with MDS. Methods In the phase II component 3 schedules of the combination were chosen based on response and adverse event profile for further evaluation. Eligible patients were entered into one of 3 cohorts with the combination (see table 1): cohort 1: azaC 55 mg/m2/d 1-7 SC, vorinostat 200mg po Bid d3-16; cohort 2: azaC 75 mg/m2/d 1-7 SC, vorinostat 300mg po Bid d3-9; cohort 3: azaC 55 mg/m2/d 1-7 SC, vorinostat 300mg po Bid d3- 9. Patients with IPSS int-1, -2 and high-risk disease were eligible. Patients with secondary MDS were eligible, those with AML were excluded. Using a simon 2 stage design 13 patients were entered in each cohort and assessed for response, scored according to IWG 2006 criteria and toxicity. Results 40 patients have been entered and 39 (21 male, 18 female) are evaluable for toxicity and 33 for response, 1 pt was registered but never treated. IPSS classification among the 39 patients: int-1 8; int-2 12; high-risk 12; unclassified 7, with median age 67 (23-79). Responses among evaluable patients have occurred in 23 of 33 (70%); 10 CR, 4 CRi, (CR+CRi=42%) 9 HI, 5 SD, 5 NR. Median time to response is 2 cycles (8 weeks). Responses by cohort (table 1) are 70%, 73% and 67% for cohort 1, 2 and 3, respectively. Analysis for the MDS clone at the time of best response demonstrated the persistence of the clone in 45% of patients as marked by cytogenetic or FISH abnormalities, suggesting a modulating rather than cytotoxic effect of the combination on the clone. Cycles administered, range from 1 to 26+ with a median of 6 cycles. Median duration of response is 16 months overall and 9.5, 23 and 27 months, respectively for cohorts 1, 2 and 3. Eighteen patients have come off study for: death or due to disease complications (6); co-morbidities (2); consent withdrawal (5); and withdrawal for stem cell transplant (3). Median OS is 21.1 months and is 10.1, 37.4 and 19 months for cohorts 1, 2, and 3 respectively (NS). Grade 3 fatigue occurred during cycle 1, 2 or 3 in cohort 1 (8%), cohort 2 (16%) and cohort 3 (8%). GI toxicity grade 3 (vomiting, diarrhea, dehydration) occurred in 8% of patients in each of the cohorts. There was no suggestion of cumulative toxicity for either fatigue or GI adverse events. Correlative biologic study analysis is underway. Conclusion The combination of azaC and vorinostat can be safely administered, and is well tolerated in repetitive cycles. The dose of azaC in cohort 2 adheres to the FDA approved dose and schedule. OR and CR rates and time to initial response are comparable among the cohorts and these data suggest that the combination is superior to published results of azaC alone. Cohorts 2 and 3, with vorinostat administered for 7 days, appears to be associated with longer response duration and OS. An intergroup study (SWOG-S1117) comparing azaC and vorinostat to either azaC alone or combined with lenalidomide is underway utilizing the doses and schedule in cohort 2 from this study. Correlative studies that may shed light on mechanism of action or guide patient selection are being conducted. Supported in part by NYCC- N01 CM-62204 and the Henry and Mickey Taub Foundation. Disclosures: Silverman: Merck: Research Funding. Off Label Use: vorinostat for treatment of patients with a myelodysplastic syndrome investigational use.

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Phase I study to evaluate the tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) of PM01183 (Lurbinectedin) in combination with olaparib in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.5573 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 5573-5573

Author(s):

Andres Poveda ◽

Ana Oaknin ◽

Ignacio Romero ◽

Angel Guerrero ◽

Lorena Fariñas-Madrid ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Phase Ii ◽

Phase I Study ◽

Brca Mutation ◽

Parp Inhibitor ◽

Single Agent ◽

Antitumoral Activity ◽

Synergistic Activity ◽

Grade 3

5573 Background: PM01183 (Lurbinectedin) is a new anticancer drug that exerts antitumor activity through inhibition of trans-activated transcription and modulation of tumor microenvironment and is highly active in platinum resistant ovarian cancer. (Poveda A et al. ASCO 2014.abstr #5505). Olaparib (AZD2281, KU-0059436) is a polyadenosine 5’diphosphoribose (poly [ADP ribose]) polymerase (PARP) inhibitor of PARP-1,-2 and-3 with proven antitumoral activity in homologous recombination deficient tumors. The combination of PM01183 and Olaparib has shown synergistic activity in cell-lines, independent of BRCA mutation status. Methods: This phase I study evaluates the safety, PK and PD of PM1183 in combination with short course of Olaparib tablet formulation [days (d) 1-5] a cycle of 21 d, through a 3+3 dose escalation design (NCT02684318) Patients with advanced or metastatic solid tumors without established standard therapeutic alternatives were selected. Primary endpoints: safety (MTD, DLT and RP2D). Secondary endpoints: PK and PD (western blot analysis of RAD51 and p-gH2AX) profiles at 0h,4.5h, 6.5h and 24h at first cycle of treatment. Results: 20 patients were enrolled from Nov 2015 to Sep 2016 (15 ovarian, 5 endometrial) to 5 dose levels. 19/20 were evaluable for toxicity. Two dose limiting toxicities (DLTs) (both grade 4 neutropenia ≥ 4 days) occurred at the highest dose level (PM01183 2 mg/m2 iv d1 + Olaparib 250 mg [BID] oral on d 1-5. Grade 3 toxicities occurred in 30% of patients, including grade 3 neutropenia (6%) and grade 3 asthenia (10%). PK data are available from 19 patients. Median of PM01183 total clearance (11.0 L/h) is the same as when PM01183 is given as single agent. Clearance of Olaparib (7 L/h) is consistent with results reported elsewhere (5.1 – 8.6 L/h). PD: An overall increase of RAD51 and p-gH2AX was observed, being particularly evident in 56% of patients. Conclusions: The Recommended Dose for Phase II (RP2D) was PM01183 1,5 mg/m2 iv d1 + Olaparib 250 mg BID on d 1-5. This combination is feasible and without evidence of drug-drug interactions. A phase-II study at RP2D is ongoing. Clinical trial information: NCT02684318.

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Preliminary Results of a Phase I/II Trial of BBR-2778 (Pixantrone) in Combination with Fludarabine, Dexamethasone, and Rituximab (FPD-R) in the Treatment of Patients with Relapsed/Refractory Indolent Non-Hodgkin’s Lymphoma (NHL).

Blood ◽

10.1182/blood.v104.11.1324.1324 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1324-1324 ◽

Cited By ~ 1

Author(s):

Luis Fayad ◽

James Liebmann ◽

Manuel Modiano ◽

Gary I. Cohen ◽

Barbara Pro ◽

...

Keyword(s):

Phase I ◽

B Cell ◽

Phase Ii ◽

Performance Status ◽

Single Agent ◽

B Cell Lymphoma ◽

Median Number ◽

Outpatient Basis ◽

Significant Activity ◽

Cardiac Events

Abstract Background: Fludarabine-mitoxantrone-dexamethasone-rituximab (FND-R) is a combination chemotherapy with significant activity in untreated and relapsed indolent B-cell lymphoma patients (pts). Pixantrone is a novel aza-anthracenedione that has no delayed cardiotoxicity in animal models and has single agent activity in NHL. We conducted an outpatient phase I/II trial, to define the recommended dose (RD) of pixantrone when substituting for mitoxantrone in the FND-R regimen, and the safety and efficacy of this regimen in pts with relapsed or refractory indolent NHL. Methods: Pts received pixantrone with fludarabine (25mg/m2/day, days 1–3), dexamethasone (20mg/day, days 1–5), and rituximab (375mg/m2/day on day 1) in a 28 day regimen (FPD-R). Based on previous single agent clinical studies, the starting dose of pixantrone was defined as 80mg/m². The RD was established to be 120mg/m2 and the protocol was amended to treat patients in the phase II part. Results: 9 pts (6 males) with a median age of 65 years (range 41–78) were included in the dose-finding part of the study. Following the protocol amendment, 23 pts (11 males) of WHO performance status 0–1, median age 61 (range 32–78) have been enrolled in the currently ongoing phase II part. Pathology included SLL/CLL, follicular grade I, follicular grade II, MALT, marginal cell, and other indolent B-cell lymphomas. All pts had received a prior anthracycline-containing regimen (median number 1, range 1–4). The study regimen was well tolerated; median number of courses received was 5 (range 2–8). Grade 4 toxicities were neutropenia in 10 pts, leukopenia in 5 pts, and thrombocytopenia in 1 pt. No clinically significant cardiac events or decreases in LVEF ≥20% were noted. However 4 pts went below 50% LVEF including 1 pt who was below 50% at baseline. Non-hematologic adverse events were primarily grade 1 or 2 in severity. Response rate was 75% for the 20 pts evaluable for response, with 11 (55%) complete remission [7 confirmed (CR), 4 unconfirmed (CRu)], and 4 (20%) partial remission (PR). Two responders went onto bone marrow transplant (BMT): one had a CRu and one a PR. A third patient was pending BMT after CR. At a median follow-up of 345 days, the median duration of response has not been reached, as only two pts have progressed: the first progression occurred at 113 days, and the second pt progressed at 699 days. The remaining pts are still in remission. Conclusions: The RD of pixantrone in the FPD-R regimen is 120mg/m2. The primary toxicity is hematologic. The regimen can be given on an outpatient basis, is associated with major responses, and is very well tolerated in relapsed and refractory indolent NHL pts.

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A Phase II Study of Temsirolimus (CCI-779) in Patients with Advanced Leukemias.

Blood ◽

10.1182/blood.v104.11.4523.4523 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4523-4523 ◽

Cited By ~ 1

Author(s):

Karen W.L. Yee ◽

Guillermo Garcia-Manero ◽

Deborah Thomas ◽

Farhad Ravandi-Kashani ◽

Srdan Verstovsek ◽

...

Keyword(s):

Disease Progression ◽

Phase Ii ◽

Phase Ii Study ◽

Blast Crisis ◽

Single Agent ◽

Mammalian Target Of Rapamycin ◽

Median Number ◽

Prior Therapy ◽

Flat Dose ◽

Grade 3

Abstract Temsirolimus (CCI-779, Wyeth Pharmaceuticals) has been shown to inhibit proliferation of a variety of tumors and induce G1 cell cycle arrest by preventing activation of the serine/threonine kinase, mTOR (mammalian target of rapamycin), a downstream effector of the PI3K/Akt pathway. Several lines of evidence implicate the PI3K/Akt/mTOR pathway in hematological malignancies. Interim results of a phase II study evaluating the efficacy and toxicity of single-agent temsirolimus in patients with advanced malignancies are presented. Temsirolimus was administered weekly, at a flat dose of 25 mg, as a 30-minute intravenous infusion. Treatment was continued until evidence of disease progression or unacceptable toxicity. To date, 8 patients have been enrolled and 7 are evaluable for efficacy and toxicity (one patient did not receive temsirolimus). Of these 7 patients, 5 had AML, 1 CML-myeloid blast crisis, and 1 ALL. Median age was 68 years (range, 21 to 87 years) and 5 were male. All patients had received prior therapy, median 2 regimens (range, 1 to 3 regimens). The median number of temsirolimus doses administered was 3 (range, 1 to 10) with a median time on study of 18 days (range, 3 to 89+ days). The most common temsirolimus-related adverse events were grade ≤ 2 and consisted of anorexia, nausea and/or vomiting and diarrhea, mucositis, dermatitis, hypertriglyceridemia, hyperglycemia, hypomagnesemia, hypocalcemia, hypokalemia, hypophosphatemia, and fatigue/asthenia. No patient developed nonspecific pneumonitis. Grade 3 toxicities included fatigue/asthenia (2), hyperglycemia (1), painful mucositis with dehydration and electrolyte abnormalities (1), diarrhea with hypokalemia (1), and hypophosphatemia (1). No patient experienced grade 4 toxicities or death from temsirolimus. No patient required dose reductions, but 2 did have dose delays due to grade 3 mucositis (1) and out-of-state hospitalization for pneumonia and atrial fibrillation (1). No patient achieved a complete remission. One patient with heavily pre-treated Philadelphia-negative precursor B-cell ALL had a transient 79% to 91% reduction in peripheral blood blasts 4 days after the first dose of temsirolimus that was maintained for 12 days prior to disease progression with involvement of the synovial fluid in bilateral knees. At the time of analysis, 6 of the 7 patients have discontinued treatment due to disease progression (4), patient refusal (1), or physician decision (1). Preliminary findings indicate that temsirolimus is relatively well-tolerated at a dose of 25 mg per week and may have biologic activity in ALL. Accrual onto the study is currently ongoing.

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Sequential Topoisomerase I (Topo I) and Topoisomerase II (Topo II) Inhibitors in Relapsed/Refractory Aggressive NHL: Results of CALGN 59906, a Phase II Study of Doxorubicin and Topotecan.

Blood ◽

10.1182/blood.v104.11.2500.2500 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2500-2500 ◽

Cited By ~ 1

Author(s):

Sonali M. Smith ◽

Jeffrey L. Johnson ◽

Donna Niedzwiecki ◽

J. Paul Eder ◽

George P. Canellos ◽

...

Keyword(s):

Phase Ii ◽

Topoisomerase I ◽

Phase Ii Study ◽

Single Agent ◽

B Cell Lymphoma ◽

Large Cell ◽

Cell Transplant ◽

Histologic Subtype ◽

Sequential Administration ◽

Topo Ii

Abstract Topoisomerase enzymes are critical components of genomic replication and function to minimize torsional stress on DNA. Inhibition of topoisomerase function leads to DNA strand breaks followed by apoptosis. In malignant lymphomas, topo II inhibitors (anthracyclines, epidophyllotoxins) are part of many active regimens, and topo I inhibitors (camptothecins) show modest single agent activity. Supported by preclinical data, we hypothesized that the sequential administration of a topo II inhibitor followed by a topo I inhibitor would be potentially synergistic, with enhanced cytotoxicity of the topo I inhibitor due to increased target enzyme levels following topo II inhibition. The treatment regimen consisted of doxorubicin 25 mg/m2 IV on day 1 and topotecan 1.75 mg/m2/d IV on days 3–5, repeated at 21 day intervals. The primary objective of this phase II study was to determine the overall response rate, time to progression, and toxicity in patients with relapsed/refractory aggressive NHL. Eligible patients had recurrent or refractory aggressive NHL, no prior camptothecins, and limited prior anthracycline exposure (<400 mg/m2 prior doxorubicin; <96 mg/m2 prior mitoxantrone), and an ejection fraction ≥ 45% at baseline. Results: From July 2000 to August 2003, 26 patients were registered. One registered patient did not start protocol treatment and is excluded from analysis. Of 22 patients with a known histologic subtype, 18 had diffuse large B cell lymphoma and there was one case each of Burkitt’s, follicular grade III, anaplastic large cell, and anaplastic large cell, Hodgkin’s like lymphoma. The median age was 58 (range 23–74) years. All patients were heavily pretreated with a median of 2 (range 1–5) prior regimens, including 5 patients who had a prior stem cell transplant (SCT). A median of 2 cycles (range 1–6) were administered. Five patients (20%, 95% CI 0.07, 0.42) responded with 1 (4%) complete remission (CR) and 4 (16%) partial remissions (PR); an additional 3 (12%) patients had stable disease. 12 (48%) patients progressed during or after the first cycle and 5 (20%) progressed after the second cycle. The one patient achieving a CR had Burkitt’s lymphoma, and received a total of 6 cycles; this patient remains in remission 21 months following the end of treatment. Of the PR patients, 2 remain in PR at 1.5 and 12 months following therapy, and 2 patients have progressed at 1.5 and 6 months. Interestingly, 4 of the 5 responders had prior SCT. The main toxicity was hematologic, with 14 (63%) and 9 (41%) patients having grade 3 or 4 neutropenia and thrombocytopenia, respectively. Three patients had febrile neutropenia. There were no treatment-related deaths. Seven patients remain alive and 18 patients have died. The median follow-up time for surviving patients is 14 (range 7–27) months. The median event-free survival is 1.3 months and the median overall survival is 3.6 months. The combination of doxorubicin and topotecan is well-tolerated and has modest activity in relapsed/refractory NHL, with an occasional patient having a prolonged remission.

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mTOR Inhibition for Relapsed or Refractory Hodgkin Lymphoma: Promising Single Agent Activity with Everolimus (RAD001).

Blood ◽

10.1182/blood.v110.11.2555.2555 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2555-2555 ◽

Cited By ~ 12

Author(s):

Patrick B. Johnston ◽

Steven M. Ansell ◽

Joseph P. Colgan ◽

Thomas M. Habermann ◽

David J. Inwards ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Phase Ii ◽

Response Rate ◽

Single Agent ◽

Mtor Inhibitors ◽

Cell Transplant ◽

Mtor Inhibition ◽

Treatment Regimens ◽

Common Grade ◽

Grade 3

Abstract Background: mTOR inhibition has produced responses in mantle cell lymphoma as well as other non-Hodgkin lymphomas. This phase II study tested the oral mTOR inhibitor everolimus (RAD001, Novartis Pharmaceuticals) in simultaneous two-stage phase II lymphoma studies, including one arm involving Hodgkin lymphoma. The goals were to learn the toxicity profile and to assess the anti-tumor response. A total of 17 patients with Hodgkin lymphoma were enrolled in the uncommon arm at completion of enrollment. Methods: Patients (pts) received 10 mg PO daily for each 28 day cycle (up to 12, with a possible extension in responders) and restaged after 2, 6, and 12 cycles. The primary endpoint is the confirmed response rate, including CR, CRu or PR. Results: The median age of the 17 pts with Hodgkin lymphoma was 37 yrs (range: 27–68), with a median of 6 (range, 4–14) prior therapies. Fourteen pts (82.4%) had a prior stem cell transplant (SCT). Pts completed a median of 6 (range, 1–13) cycles of therapy. Fifteen of 17 patients were evaluable for response as of this analysis. The overall response rate was 47% (7/15), all partial responses. Ten patients are continuing on study while 6 have gone off due to disease progression and 1 due to other reasons. Common grade 3 adverse events (AEs) include thrombocytopenia (5 pts), anemia (5 pts) and alkaline phosphatase elevation (1 pts). 1 patient was reported to have grade 4 neutropenia. Conclusions: Oral everolimus has promising activity with acceptable toxicity in Hodgkin lymphoma. These results provide the rationale for additional studies with this novel class of agents and to integrate mTOR inhibitors into salvage treatment regimens for Hodgkin lymphoma.

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A Phase II Multicenter Study of the Histone Deacetylase Inhibitor (HDACi) Abexinostat (PCI-24781) in Relapsed/Refractory Follicular Lymphoma (FL) and Mantle Cell Lymphoma (MCL)

Blood ◽

10.1182/blood.v120.21.55.55 ◽

2012 ◽

Vol 120 (21) ◽

pp. 55-55 ◽

Cited By ~ 9

Author(s):

Andrew M. Evens ◽

Julie M Vose ◽

Wael Harb ◽

Leo I. Gordon ◽

Robert Langdon ◽

...

Keyword(s):

Phase I ◽

Phase Ii ◽

Safety Profile ◽

Tumor Size ◽

Phase Ii Study ◽

Cell Lymphoma ◽

Single Agent ◽

Employment Equity ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 55 Background: Abexinostat (PCI-24781) is a novel oral pan-HDACi that has previously demonstrated potent preclinical activity in lymphoma cell lines and animal models (Evens et al, Clin Ca Res 2009) as well as a tolerable safety profile in phase I solid tumor clinical studies (Undevia et al, ASCO 2008). In a phase I single-agent clinical trial in patients (pts) with multiply relapsed/refractory lymphoma and leukemia, anti-tumor activity was noted in FL and MCL; 4/4 FL pts showed durable clinical benefit with median time on treatment of >8 months; 1 of 2 MCL pts had a complete remission (CR) and remains on treatment for >3 years. Based on these encouraging single-agent abexinostat data, a phase II extension study was completed in relapsed/refractory FL and MCL. Methods: The primary objective of this phase II study was objective response rate (ORR, complete [CR] and partial remission [PR]), while reduction in tumor size (CR + PR + stable disease) and safety were also examined. Abexinostat was given orally twice daily at 45mg/m2 on a 4-week cycle for 7 days/week every other week, which is the previously established dose and schedule identified in the phase I study. For pharmacodynamic correlative analyses, tubulin and histone acetylation were measured in peripheral blood mononuclear cells (PBMCs) at pre-dose and 4 hours after the first dose of abexinostat. Results: A total of 30 pts were enrolled (n=16 FL and n=14 MCL pts) of which 25 were response-evaluable. The median age was 67 years (36–81) and the median prior therapies were 3 (1–5), 77% of which were rituximab-containing and one-third (33%) had undergone prior autologous stem cell transplant (31% FL, 36% MCL). The ORR in all pts was 48% (12/25). A reduction in tumor size was observed in 86% (12/14) of FL pts, while the ORR in FL was 64% (9/14); the FL intent-to-treat ORR was 56%. With a median follow-up of 10.3 months (1.2–20.9), the progression-free probability was 86% in FL pts. Furthermore, the median duration of response (DOR) in FL pts has not been reached, as 5 responders remain on study. Notably, 4 FL pts were on treatment for over 16 months. Among MCL pts, reduction in tumor size was noted in 27% (3/11), while the ORR was similar at 27% (3/11). The median progression-free survival (PFS) in MCL pts was 4 months (1–12), while the DOR in the 3 responding patients were 2+, 3, and 6+ months. Therapy was overall well tolerated. The most common treatment-related adverse events (AEs) of any grade (> 20% incidence) include: nausea (60%), fatigue (57%), diarrhea (50%), thrombocytopenia (37%), vomiting (30%), anemia (27%), decreased appetite (23%), dysgeusia (20%) and neutropenia (20%). The most common grade 3/4 related AEs (> 5% incidence) were thrombocytopenia (17%), neutropenia (13%), fatigue (13%), and anemia (7%). There were no deaths reported on the study. Pharmacodynamic analyses revealed that a majority of pts had increased tubulin acetylation in PBMCs, however this finding did not correlate with response or toxicity. Conclusion: In this phase II study, the novel pan-HDACi, abexinostat, was clinically active and overall well tolerated in relapsed/refractory B-cell lymphoma. The safety profile was consistent with this class of agents with <20% of subjects experiencing grade 3/4 cytopenias (during the course of prolonged treatments). Moreover, there was significant clinical activity noted in FL with an ORR of 64%, which included several durable responses in this multiply-relapsed pt population. Further examination of single-agent abexinostat in FL is warranted. Disclosures: Off Label Use: PCI24781 is not FDA approved; it is an investigational agent. Plasencia:Pharmacyclics: Employment, Equity Ownership. Sirisawad:Pharmacyclics: Employment, Equity Ownership. Yue:Pharmacyclics: Employment, Equity Ownership. Luan:Pharmacyclics: Employment, Equity Ownership. Siek:Pharmacyclics: Employment, Equity Ownership. Zhou:Pharmacyclics: Consultancy. Balasubramanian:Pharmacyclics: Employment, Equity Ownership.

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