Activity of Combined Flavopiridol and Lenalidomide in Patients with Cytogenetically High Risk Chronic Lymphocytic Leukemia (CLL): Updated Results of a Phase I Trial,

Abstract Abstract 3910 Background: The cyclin dependent kinase inhibitor, flavopiridol, and the immunomodulatory agent, lenalidomide, are active in heavily pre-treated CLL patients (pts) with bulky adenopathy and adverse cytogenetics, although dose escalation of these two agents has been limited by tumor lysis syndrome (TLS) and tumor flare. Furthermore, these agents do not deplete T-cells, and combination therapy may result in greater efficacy and less infectious toxicity than observed with fludarabine or alemtuzumab combinations. Methods: We conducted a phase I trial of combined flavopiridol and lenalidomide in pts with CLL relapsed after at least 1 prior therapy, WBC < 150,000/mm3, ANC > 1000/mm3, platelets > 30,000/mm3, and creatinine < 1.5 mg/dL. Treatment consisted of flavopiridol alone, 30 mg/m2 bolus + 30–50 mg/m2 4-hour continuous IV infusion (CIVI) days 1, 8, and 15 of cycle 1. Starting in cycle 2, flavopiridol 30 mg/m2 bolus + 30–50 mg/m2 4-hour CIVI days 3, 10, and 17 was combined with lenalidomide 2.5, 5.0, 7.5, 10, 15, or 25 mg days 1–21 every 35 days. All pts received 20 and 4 mg of dexamethasone 30 minutes prior to and 24 hours after flavopiridol, respectively, to minimize cytokine release symptoms. Pegfilgrastim was administered on day 18 of cycles 2–8. Results : Thirty pts (18 males) with a median age of 60 (range 42–74) previously treated with a median of 3 prior therapies (range 1–10) were enrolled. All pts received prior fludarabine and 40% were fludarabine refractory. Seventy-three percent of patients were Rai stages III-IV, 60% pts had bulky adenopathy > 5 cm, 60% pts had del(17p13.1), 37% pts had del(11q22.3), and 83% pts had a complex karotype. Twenty-five pts completed two or more cycles of therapy (median 3.5, range 1–8). Five pts completed only one cycle of therapy and were removed prior to receiving lenalidomide due to progressive disease (n=2), TLS requiring dialysis (n=2), and grade 4 thrombocytopenia (n=1). Pts received 2.5 mg (n=6), 5.0 mg (n=7), 7.5 mg (n=4), and 10 mg (n=3) of lenalidomide with 30 mg/m2 bolus + 30 mg/m2 4-hour CIVI flavopiridol and 5 patients have received 10 mg of lenalidomide with 30 mg/m2 bolus + 50 mg/m2 4-hour CIVI flavopiridol. DLT consisting of grade 3–4 transaminitis persisting > 7 days occurred in 2 pts treated with 2.5 mg (n=1) and 5.0 mg of lenalidomide (n=1), respectively. Grade 3–4 toxicities consisted of thrombocytopenia (60%), diarrhea (57%), transient transaminitis (47%), neutropenia (47%), hyperglycemia (47%), infection (43%, pneumonia in 5 pts, upper respiratory tract infection in 2 pts, cellulitis in 1 pt, herpes simplex stomatitis in 1 pt, oral candidiasis in 1 pt, catheter-associated in 1 pt, and febrile neutropenia without a source in 2 pts), hypokalemia (37%), anemia (33%), hypophosphatemia (33%), hypocalcemia (17%), hyperkalemia (17%), TLS requiring dialysis (7%), tumor flare (3%), and rash (3%). In 23 evaluable pts who completed 1 or more cycles of combined lenalidomide and flavopiridol, partial responses were observed in 13 pts (57%), including 7 pts with del(17p13.1), 6 pts with del(11q22.3), 9 pts with complex cytogenetics, 5 fludarabine-refractory pts, and 6 pts with bulky lymphadenopathy. Six pts were able to proceed to allogeneic transplant after 1–3 cycles, and 4 of these pts remain in remission. Median PFS and OS are 7 months (range 0–24 months; 95% CI 5, 11) and 23 months (range 0–27 months; 95% CI 13, 27), respectively. No significant differences have been observed in the single agent and combination PK parameters (AUC, Cmax, T ½, and Clearance) of lenalidomide and flavopiridol. Conclusions: Combined flavopiridol and lenalidomide is well tolerated without increased risks of TLS or tumor flare, with significant activity in pts with bulky, cytogenetically high-risk CLL. This combination regimen could be utilized to de-bulk high risk pts prior to stem cell transplantation or prior to other oral therapies. The MTD has not been reached and dose escalation continues at a lenalidomide dose that exceeds the single agent MTD in CLL of 5 mg (Maddocks et al, Blood 114: abstract 3445, 2009). Future evaluation of continued maintenance lenalidomide after initial combination therapy is planned. This trial is supported by NCI 1R21 CA133875, NCI P50-CA140158, NCI K23 CA109004, NCI U01 CA076576, LLS SCOR 7080–06, and the D. Warren Brown Foundation. Disclosures: Off Label Use: Flavopiridol and lenalidomide are off-label for the treatment of CLL.

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Phase I Trial of Oral Irinotecan and Temozolomide for Children With Relapsed High-Risk Neuroblastoma: A New Approach to Neuroblastoma Therapy Consortium Study

Journal of Clinical Oncology ◽

10.1200/jco.2008.18.5918 ◽

2009 ◽

Vol 27 (8) ◽

pp. 1290-1296 ◽

Cited By ~ 60

Author(s):

Lars M. Wagner ◽

Judith G. Villablanca ◽

Clinton F. Stewart ◽

Kristine R. Crews ◽

Susan Groshen ◽

...

Keyword(s):

High Risk ◽

Phase I ◽

Phase I Trial ◽

Single Agent ◽

Complete Response ◽

Maximum Tolerated Dose ◽

Time Curve ◽

Disease Stabilization ◽

Heavily Pretreated ◽

Grade 3

PurposeIrinotecan and temozolomide have single-agent activity and schedule-dependent synergy against neuroblastoma. Because protracted administration of intravenous irinotecan is costly and inconvenient, we sought to determine the maximum-tolerated dose (MTD) of oral irinotecan combined with temozolomide in children with recurrent/resistant high-risk neuroblastoma.Patients and MethodsPatients received oral temozolomide on days 1 through 5 combined with oral irinotecan on days 1 through 5 and 8 through 12 in 3-week courses. Daily oral cefixime was used to reduce irinotecan-associated diarrhea.ResultsFourteen assessable patients received 75 courses. Because neutropenia and thrombocytopenia were initially dose-limiting, temozolomide was reduced from 100 to 75 mg/m2/d for subsequent patients. Irinotecan was then escalated from 30 to 60 mg/m2/d. First-course grade 3 diarrhea was dose-limiting in one of six patients treated at the irinotecan MTD of 60 mg/m2/d. Other toxicities were mild and reversible. The median SN-38 lactone area under the plasma concentration versus time curve at this dose was 72 ng · hr/mL. One patient with bulky soft tissue disease had a complete response through six courses. Six additional patients received a median of seven courses (range, three to 22 courses) before progression.ConclusionThis all-oral regimen was feasible and well tolerated in heavily pretreated children with resistant neuroblastoma, and seven (50%) of 14 assessable patients had response or disease stabilization for three or more courses in this phase I trial. SN-38 lactone exposures were similar to those reported with protracted intravenous irinotecan. The dosages recommended for further study in this patient population are temozolomide 75 mg/m2/d plus irinotecan 60 mg/m2/d when given with cefixime.

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Rituximab, Cyclophosphamide, Bortezomib and Prednisone (R-CBorP): Final Results of a Phase I Trial Evaluating Two Dosing Schedules and the Safety of Overlapping Pegfilgrastim in Patients with Relapsed/Refractory Indolent and Mantle Cell Lymphomas.

Blood ◽

10.1182/blood.v114.22.3708.3708 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3708-3708 ◽

Cited By ~ 1

Author(s):

John Gerecitano ◽

Carol S. Portlock ◽

Paul A. Hamlin ◽

Craig H Moskowitz ◽

Ariela Noy ◽

...

Keyword(s):

Phase I ◽

Phase I Trial ◽

Single Agent ◽

Response Rates ◽

Neutropenic Fever ◽

Significant Activity ◽

Weekly Schedule ◽

Mantle Cell ◽

Grade 3 ◽

Weekly Group

Abstract Abstract 3708 Poster Board III-644 Aim To determine the safety and efficacy of substituting bortezomib (Bor) for vincristine in standard ‘R-CVP’. A separate safety analysis evaluated the safety of pegfilgrastim (PegG) overlapping with Bor administration. Rationale Vincristine has marginal activity in indolent lymphomas, while preclinical and clinical data suggest that single agent Bor has significant activity in indolent and mantle cell (MCL) non-Hodgkin Lymphoma (NHL), and may also be synergistic with rituximab (R) and DNA-damaging agents. Methods In this phase I trial, Bor and cyclophosphamide (C) were alternately escalated. R (375 mg/m2) and C (750 mg/m2 or 1000 mg/m2) were dosed on day one, and prednisone (P) (100 mg daily) on days 2-6. In schedule 1, Bor was given on days 2 and 8, with doses escalated from 1.3 to 1.8 mg/m2. In schedule 2, Bor was given on days 2, 5, 9 and 12 with doses escalated from 1.1 to 1.5 mg/m2. Due to 2 neutropenic fevers in schedule 2 (twice-weekly Bor), the protocol was amended to allow for filgrastim (G) support, administered in between Bor dosing days. This allowed accrual to the highest planned dosing level. A separate cohort of 10 patients was added at the twice-weekly Bor 1.3 mg/m2 + C 1000 mg/m2 level to assess the safety of administering overlapping PegG instead of G. In this cohort, PegG was given with Bor on day 2. Patients with PR or SD after 4 cycles received 4 further cycles, those with CR got 2 further cycles. Toxicity was assessed using NCI-CTC, v. 3.0. No DLT was seen at maximum doses of Bor and C in either schedule. Schedule 1 accrued 15 patients, with one DLT requiring cohort expansion at the second dose level. Schedule 2 accrued 40 patients. Results Demographic variables were similar between the two groups, and both schedules were well tolerated with similar toxicity profiles. Most hematologic toxicities (HTs) and non-HTs across all dose levels and cycles were grade 1-2. Grade 3-4 non-HTs in the weekly treatment cohorts included grade 3 diarrhea (n=1), dehydration (n=1), neutropenic fever (n=1), infection (n=2) and anal incontinence (n=1, likely unrelated). Grade 3 toxicities in the twice-weekly groups included fatigue (n=3), neutropenic fever (n=2), fever (n=1), hypoxia (n=1) and neuropathy (n=2), along with one grade 4 neuropathy. Of the patients who developed neuropathy above baseline, resolution to baseline occurred in 8 of 9 (89%) of patients in the weekly group after a median of 0.7 months, and in 15 of 26 (58%) of patients in the twice-weekly group after a median of 4 months. To evaluate the safety of pegfilgrastim overlapping with 4 doses of Bor, toxicities and CBCs for patients in the PegG group were compared with those of patients treated at identical doses of R-CBorP given non-overlapping G support. All toxicities and CBC trends were similar, with the exception of a significant but mild decline in platelets in the PegG group. Overall response rates in the 13 evaluable weekly and 33 evaluable twice-weekly patients were 46% (23% CR) and 64% (36% CR), respectively. Conclusions R-CBorP is a well-tolerated and promising new regimen in patients with NHL. The safety of administering PegG overlapping with Bor has been established, and simplifies this regimen. Although response rates appeared to be greater in the twice-weekly schedule, a randomized study will be required to determine the true difference. Grade 3-4 neuropathy was seen only in the twice-weekly dosing group, and seemed to be less reversible and longer-lasting than in the weekly group. A randomized phase II study will soon begin enrollment to compare the toxicity and efficacy of these two dosing schedules in a larger group of patients with follicular lymphoma. Disclosures: Gerecitano: Genentech: Speakers Bureau; Biogen Idec: Speakers Bureau. Off Label Use: bortezomib in combination with other active agents for indolent and mantle cell non-Hodgkin lymphomas. Hamlin:Genentech: Speakers Bureau; Biogen Idec: Speakers Bureau. Zelenetz:Millenium Advisory board: Membership on an entity's Board of Directors or advisory committees.

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Abstract CT214: ATRiUM: A first-in-human dose escalation phase I trial of ceralasertib (AZD6738) and gemcitabine as combination therapy

10.1158/1538-7445.am2021-ct214 ◽

2021 ◽

Author(s):

Bruno Henrique de Paula ◽

Bristi Basu ◽

Adrian Mander ◽

Josephine Khan ◽

Purity Bundi ◽

...

Keyword(s):

Combination Therapy ◽

Phase I ◽

Dose Escalation ◽

Phase I Trial ◽

Human Dose

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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, Dose-Escalation Study of 2 Dosing Regimens of AS703569, An Inhibitor of Aurora and Other Kinases, Administered Orally in Patients with Advanced Hematological Malignancies

Blood ◽

10.1182/blood.v112.11.2963.2963 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2963-2963 ◽

Cited By ~ 6

Author(s):

Anne Sonet ◽

Carlos Graux ◽

Johan Maertens ◽

Christine-Maria Hartog ◽

Justus Duyster ◽

...

Keyword(s):

Phase I ◽

Dose Escalation ◽

Preliminary Data ◽

Hematological Malignancies ◽

Single Agent ◽

Gi Bleeding ◽

Dose Escalation Study ◽

Inhibition Of Proliferation ◽

Dosing Regimens ◽

Grade 3

Abstract Background: AS703569 is a novel, orally bioavailable, potent ATP-competitive, small molecule that inhibits all three aurora kinase isoforms (A, B, and C), and shows inhibitory activity across other kinases involved in cell proliferation and survival, including FLT3, ABL1, ABL1 (mut. T315I), JAK-2, and FGFR3. AS703569 has been tested as a single agent and in combination with standard-of-care anticancer agents in leukemia cell lines, freshly isolated leukemic cells, and tumor xenograft models. The strong inhibition of proliferation and the triggering of apoptosis induced by AS703569 lead to significant anti tumor activity resulting in tumor regression or growth delay, and prolongation of animal survival. AS703569 is currently being tested in phase I studies as a single agent and in combination; the main objectives are to establish the MTD (based on dose-limiting toxicities [DLTs]) and evaluate the safety and PK/PD effects of different regimens. Study design: This is an open-label, phase I, two-arm, dose-escalation study in patients (pts) with AML, CML, MDS, and MPD. Patients were sequentially assigned to one of two AS703569 dosing regimens: Regimen 1: once daily (QD), days 1–3 and 8–10 of a 21-day cycle; Regimen 2: QD, days 1–6 of a 21-day cycle. In both treatment arms, AS703569 was administered at escalating dose levels (DL; 3, 6, 10, 15, 21, 28, and 47 mg/m2/day) using a 3+3 cohort design. Repeated cycles were permitted until disease progression or unacceptable toxicity. Patient characteristics: Pt characteristics are summarized in the Table. Pts had primary AML (n=20), secondary AML (n=13), CML (n=6), MDS (n=5), and MPD (n=1). Pts were heavily pretreated and had failed previous chemotherapy. Safety: The median number of AS703569 cycles received per pt was 2 for Regimen 1 (range 1–7) and 1 for Regimen 2 (range 1–6). In Regimen 1, at DL 7 (47 mg/m2/day, n=3), 2 subjects reported DLTs: 1 case of grade 3 diarrhea with hyponatremia and sepsis with a fatal outcome, and 1 case of grade 3 diarrhea with GI bleeding. In Regimen 2, at DL 7 (n=5), 3 subjects reported DLTs: 2 cases of grade 4 mucositis and 1 case of neutropenic infection. Consequently, the dose was de-escalated to 37 mg/m2/day for both regimens and enrollment is ongoing at this DL to confirm the MTD. Grade ≥3 toxicities reported throughout the study mainly included infections (18 pts), neutropenia and febrile neutropenia (17 pts), thrombocytopenia (15 pts), anemia (11 pts), and GI disorders including mucositis, diarrhea and GI bleeding (8 pts). Alopecia was reported in some pts. PK: Preliminary data for 37 pts (DL 1–6) show an increased exposure with dose, a Tmax of 2–4 h (range 0.5–8 h), and an effective half-life of ~10–20 h. Activity (preliminary data): In Regimen 1, 1 pt with refractory CML (mut. T315I) has received 7 treatment cycles and shown a hematological and cytogenetic response; 5 pts with AML received 5–7 cycles, 3 achieved reduction in BM and/or peripheral blasts. In Regimen 2, 1 pt with MDS received 6 cycles and achieved a PR; 2 pts with AML received 3 cycles and did not progress. Conclusions: These data indicate that AS703569, QD, days 1–3 and 8–10 every 21 days or on days 1–6 every 21 days is generally well tolerated in pts with advanced hematological malignancies. Most grade 3/4 toxicities are commonly seen in pts with advanced hematological malignancies and are in part linked to the underlying disease. A DL with an unacceptable frequency of DLTs was reached and enrollment continues at a lower DL to confirm the MTD. Early evidence of activity was observed in pts with CML, AML, and MDS. Regimen 1 Regimen 2 N 24 21 Median (range) age, years 69.5 (48–83) 71 (49–82) Sex, M/F 15/9 12/9 ECOG PS, 0-1-2 5-12-7 3-12-6 Median (range) previous lines of therapy 3 (1–6) 2 (1–6)

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Phase I Trial Examining Addition of Gemcitabine to CHOP in Intermediate Grade NHL.

Blood ◽

10.1182/blood.v114.22.4765.4765 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4765-4765

Author(s):

John L. Reagan ◽

James N. Butera ◽

Alan G. Rosmarin ◽

Ahmed Nadeem ◽

Fred J. Schiffman ◽

...

Keyword(s):

Febrile Neutropenia ◽

Phase I ◽

Phase I Trial ◽

Single Agent ◽

Maximum Tolerated Dose ◽

Chop Chemotherapy ◽

Intermediate Grade ◽

Chemotherapeutic Regimen ◽

Grade 3 ◽

Dose Limiting Toxicity

Abstract Abstract 4765 BACKGROUND Gemcitabine induces a 20% response as single agent therapy in patients with relapsed or refractory NHL. We report phase I findings of gemcitabine in combination with standard CHOP chemotherapy with G-CSF support for intermediate grade NHL. The protocol was modified during enrollment to include rituximab in CD 20+ lymphomas. METHODS Patients received CHOP plus gemcitabine at 500 mg/m2 (Cohort 1) or 750 mg/m2 (Cohort 2) on days 1,4 of each 21 day cycle. Accrual was suspended once each cohort was filled. Dose escalation occurred after all patients in the cohort were determined to not have a dose limiting toxicity. RESULTS Between 4/02 and 5/04 10 patients were enrolled and completed the study treatment (6 in cohort 1, 4 in cohort 2). In Cohort 1, grade 3 toxicities included neutropenia, anemia, neuropathy, and constipation. Grade 4 toxicities were febrile neutropenia, and thrombocytopenia. In Cohort 2, grade 3 toxicities included neutropenia, thrombocytopenia, mucositis, anemia and intestinal obstruction. Grade 4 toxicities included febrile neutropenia, neutropenia, and thrombocytopenia. One patient developed MDS 36 months after chemotherapy. Three of four patients in Cohort 2 developed dose limiting toxicities (mucositis and thrombocytopenia) requiring dose reduction of gemcitabine after cycle 1. Overall, the survival rate at 2.5 years was 71%. CONCLUSIONS This Phase I trial concludes that gemcitabine 500mg/m2 on days 1 and 4 of each 21 day cycle is the maximum tolerated dose when combined with standard CHOP chemotherapy with G-CSF support for intermediate grade NHL. Response rates are encouraging for this novel chemotherapeutic regimen. Disclosures: Off Label Use: Gemcitabine was added to standard CHOP chemotherapy in this trial.. Sikov:Eli Lilly: Honoraria.

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A Phase I Study of a Combination of 5-Azacyitidine Followed by Lenalidomide In High-Risk MDS or AML Patients with Chromosome 5 Abnormalities – Interim Results of the “AZALE” Trial

Blood ◽

10.1182/blood.v116.21.4000.4000 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4000-4000 ◽

Cited By ~ 2

Author(s):

Uwe Platzbecker ◽

Detlef Haase ◽

Friederike Braulke ◽

Gesine Bug ◽

Katharina Götze ◽

...

Keyword(s):

High Risk ◽

Phase I ◽

Board Of Directors ◽

Single Agent ◽

Rapid Progression ◽

Chromosome 5 ◽

Advisory Committees ◽

Cytogenetic Remission ◽

Grade 3 ◽

Ongoing Phase

Abstract Abstract 4000 Lenalidomide has shown single agent activity in patients with MDS (Myelodysplastic Syndromes) and a del(5q) cytogenetic abnormality. Further, studies with the DNA methyltransferase inhibitor 5-azacytidine (5-aza) have been conducted in high-risk MDS (IPSS INT-2 or HIGH) and patients with acute myeloid leukemia (AML) resulting in considerable responses with a low rate of extramedullary toxicity compared to conventional induction chemotherapy (IC). Given the poor outcome of high-risk MDS and AML patients with chromosome 5 abnormalities, there is a significant clinical need to perform studies with new regimens in this patient population. We report first results of an ongoing phase I clinical trial evaluating the maximum tolerated dose (MTD) of lenalidomide in combination with 5-aza in patients with either high-risk MDS, refractory/relapsed AML or de novo AML not eligible for conventional IC with chromosome 5 abnormalities including monosomy 5 or del(5q). Given the mechanism of action of both drugs and also in contrast to a recent study in non-del(5q) MDS patients, a sequential approach was chosen. In fact, induction therapy consisted of 5-aza (75mg/m2 days 1–5) followed by increasing doses of lenalidomide (starting with 10mg p.o., days 6–19). In patients achieving a complete remission this was followed by a combined maintenance therapy every 8 weeks until disease progression. To determine the MTD, a standard “3+3” design was used. The dose limiting toxicity (DLT) is determined during the first cycle only and is defined as either inability to deliver the full dosing schedule of lenalidomide due to any ≥ Grade 3 non-hematologic toxicity or absence of hematological recovery after completing the 1st cycle despite complete marrow blast clearance or treatment delay of ≥ 4 weeks as a result of unresolved grade 4 non-hematological toxicity. Of 8 patients currently enrolled, median age was 67 years (range, 45 to 74 years), interval from primary MDS or AML diagnosis was 9 months (range, 1 to 100 months). IPSS categories were INT-2 (n = 1) and HIGH (n = 3) whereas 4 patients were included with advanced AML. It is of note, that all but two patients had a complex karyotype including a del(5q) abnormality. Prior treatment included IC (n=1), IC plus allogeneic HSCT (n=3) and/or single agent 5-aza (n=3) while 4 patients had received supportive care only prior to study entry. A median of 2 induction cycles were administered. During the first cycle of cohort I (10mg lenalidomide) and cohort II (15mg lenalidomide) grades 3 to 4 non-hematologic toxicities included febrile neutropenia (n = 3), enterocolitis (n = 1) and pneumonia (n=3) whereas therapy-induced grade 3–4 neutropenia or thrombocytopenia occurred in four and five patients, respectively. The MTD has not been reached yet. One patient (12.5%) with AML showed rapid progression while receiving the 1st cycle. Out of the remaining seven patients, one (12.5%) achieved a marrow CR together with a partial cytogenetic remission, and six patients (75%) had stable disease. Interestingly, two out of these achieved a partial cytogenetic remission. These preliminary data of an ongoing phase I trial demonstrate the safety and the potential of a combination of 5-aza and lenalidomide in patients with advanced MDS or AML and a del(5q). Disclosures: Platzbecker: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Haase:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Götze:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kuendgen:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Giagounidis:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hofmann:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Mitoxantrone, Etoposide, and Cytarabine (MEC) Following Epigenetic Priming with Decitabine in Adults with Relapsed/Refractory Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS): A Phase 1 Study

Blood ◽

10.1182/blood.v124.21.3730.3730 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3730-3730

Author(s):

Anna B. Halpern ◽

Elihu H. Estey ◽

Megan Othus ◽

Kaysey F. Orlowski ◽

Morgan A. Powell ◽

...

Keyword(s):

High Risk ◽

Febrile Neutropenia ◽

Dose Escalation ◽

Salvage Therapy ◽

Hematologic Toxicity ◽

Refractory Disease ◽

Off Label Use ◽

Off Label ◽

Grade 3 ◽

Refractory Aml

Abstract Background: Most adults with AML or high-risk MDS will ultimately require salvage therapy. However, the likelihood of achieving a complete remission (CR) with standard salvage regimens is often 15-20% or less. Emerging data suggest that pre-treatment (“priming”) with a hypomethylating agent such as decitabine can sensitize AML cells to chemotherapeutics, prompting a dose-escalation study of MEC preceded by decitabine-priming in relapsed/refractory AML and high-risk MDS. Methods: This single arm study aimed to estimate the maximum tolerated dose (MTD) of decitabine-primed MEC in adults ≥18 years with relapsed/refractory high-risk MDS (>10% blasts) or AML requiring first or subsequent salvage therapy. Previous treatment with hypomethylating agents or MEC (but not the combination) was acceptable. Trial participation required a treatment-related mortality (TRM) score of <9.2, corresponding to an expected TRM of 4% with standard induction chemotherapy. Patients with post-transplant relapse were eligible if graft-versus host disease was well controlled. Excluded were patients with concomitant illness with expected survival <1 year, and active, uncontrolled infection. Cohorts of 6-12 patients were assigned to 1 of 3 total dose levels of decitabine (20mg/m2 for 5, 7, or 10 days) followed by MEC (mitoxantrone 8mg/m2/day x 5 days; etoposide 100 mg/m2/day x 5 days; cytarabine 1 g/m2/day x 5 days) after a break of 5 days. In the case of persistent leukemia, patients were eligible for re-induction provided all non-hematologic toxicities had resolved to grade <2. Patients achieving a CR or CR with incomplete platelet recovery (CRp) could receive 2 additional cycles of decitabine-MEC given at doses identical to those used during induction. Dose-limiting toxicity (DLT) was defined as: 1) any grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7 day delay of the subsequent treatment cycle, with the exception of febrile neutropenia or infection; 2) any grade ≥4 non-hematologic toxicity, with the exception of febrile neutropenia/infection or constitutional symptoms, if recovery to grade ≤2 within 14 days. Results: 30 patients, median age 55 (range: 19-72) years, with primary refractory disease (n=13), first relapse (n=16), or second relapse (n=1) with median duration of prior CR of 4 (range: 1-19) months were enrolled and received a median of 1 (range: 1-3) cycles of therapy. During dose escalation, 1 DLT occurred at each the 2nd and 3rd tested dose level after cycle 1 (septic shock with multi-organ failure in both), identifying a 10-day course of decitabine together with standard dose MEC as the MTD. A total of 12 patients received therapy at the MTD level. 9/30 patients achieved a CR (30%). This CR rate compared favorably relative to a historic control population with patient matching based on duration of prior remission and number of prior salvage therapies (Blood 1996; 88:756), with an observed/expected CR ratio of 1.9. 5 additional patients achieved a CRp, and 1 achieved a CR with incomplete count recovery (CRi) for an overall response rate of 15/30 (50%). Furthermore, 4 patients achieved a morphologic leukemia-free state, 8 had refractory disease, and 3 died before a response was assessed. Of the 15 patients who achieved a remission, 3 remain on study, 9 were taken off protocol to pursue further intensive consolidation therapy including hematopoietic cell transplantation, and 3 have died after a median CR duration of 68 days. In the 15 responders, the median response duration was 68 days (range 0-437), with 6 of these responses ongoing. Overall survival of these 15 patients was longer (median of 211 [range: 59-484] days) than that for patients who failed to achieve remission but lived at least 29 days (i.e. did not experience TRM) (median of 110 [range: 30-303] days). Six patients died within 28 days of treatment initiation for a TRM rate of 20%: 4 from infection, 1 from intracranial hemorrhage, and 1 from unknown cause. Besides grade 3-4 cytopenias, cough, fatigue, nausea and infection/neutropenic fever were the most common adverse events. Conclusion: Decitabine-primed MEC is feasible, well tolerated, and has anti-leukemic activity in relapsed/refractory AML and high-risk MDS. A phase 2 study based on these findings has been initiated. Disclosures Off Label Use: Off-label use of some of the study drugs for either AML or high-risk MDS.

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Phase I study of tipifarnib and sorafenib in patients with biopsiable advanced cancers (NCI protocol 7156 supported by NCI grant UO1 CA062461)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.3549 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 3549-3549 ◽

Cited By ~ 6

Author(s):

D. S. Hong ◽

L. Camacho ◽

C. Ng ◽

J. Wright ◽

R. A. Newman ◽

...

Keyword(s):

Phase I ◽

Skin Rash ◽

Dose Escalation ◽

Phase I Study ◽

Mapk Pathway ◽

Synergistic Effects ◽

Single Agent ◽

Unknown Primary ◽

Advanced Cancer Patients ◽

Grade 3

3549 Background: The Ras and Raf kinases are sequential signaling proteins in the MAPK pathway and inhibition of both targets may confer synergistic effects, particularly in tumors with activation of either kinase through mutation or other mechanisms. Therefore, we sought to combine sorafenib, a multikinase inhibitor (Raf, VEGFR, PDGFR) and tipifarnib an inhibitor of farnesyltransferase that is critical for Ras activity in a phase I study to determine the safety, pharmacokinetics (PK), and tumor response. Methods: The trial was a phase I trial of advanced cancer patients(pts) with a conventional dose escalation design. Each cycle consisted of 28 days of sorafenib and 21 days of tipifarnib. Dose levels are listed in the table . Results: To date, a total of 27 pts have been enrolled (median age 54.5 yrs, M:F 1:1. 3 RCC, 3 breast, 4 sarcoma, 4 melanoma, 3 CRC, 4 thyroid, 2 H&N, one thymic, one adrenal cortical, one SCC of the lung, and one unknown primary SCC). Two pts developed grade 3 DLT-skin rash on the first dosing level (tipifarnib at 100 mg po BID and sorafenib at 400 mg po BID). Dose escalation was modified as per table below. At dose level 4, 2/5 pts entered experienced a DLT of grade 3 rash and grade 3 drug fever, therefore MTD has been determined to be tipifarnib 100 mg BID, sorafenib 400 mg qam, 200 mg qpm. The most common treatment related toxicities included lymphopenia (18), hyperglycemia (17), and skin rash (14). Currently, 19 of the 27 pts are evaluable; 13 pts had SD (8–44 weeks); 2 RCC pts for 32 weeks, an adrenal cortical ca pt for 32 weeks, one melanoma pt for 44 weeks. PK analysis suggested findings similar to single agent PK profiles, no PK interactions were apparent. Conclusions: Significant toxicity with the combination of these two agents, even doses well below single agent maximum levels were observed. The MTD was determined to be tipifarnib at 100 mg BID, sorafenib at 400 mg qam, 200 mg qpm. PK analysis, to date show,no pharmacokinetic interaction between tipifarnib and sorafenib. [Table: see text] [Table: see text]

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Phase I trial of escalating doses of weekly everolimus (RAD001) in combination with docetaxel for the treatment of metastatic breast cancer (MBC)

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.1066 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 1066-1066

Author(s):

S. L. Moulder ◽

E. Rivera ◽

J. Ensor ◽

A. Gonzalez-Angulo ◽

M. Christofanilli ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Phase I ◽

Phase I Trial ◽

Single Agent ◽

Metastatic Breast ◽

Maximum Tolerated Dose ◽

Entire Group ◽

Interpatient Variability ◽

Grade 3

1066 Background: Inhibition of mTOR with everolimus (E) may improve efficacy in combination with docetaxel (D), but both drugs are metabolized by CYP3A4, thus a pharmacokinetic (PK) interaction may also exist. Methods: 15 patients (pts) with MBC were treated with docetaxel and everolimus using the continuous reassessment method (CRM) to determine maximum tolerated dose (MTD). Docetaxel doses were 40–75 mg/m2 IV on day 1 of a 21 day cycle. Everolimus doses were 20–50 mg PO on days 1 and 8 of a 21 day cycle (except cycle 2, where only day 8 was given to allow single agent PK analyses of both drugs). Response was measured every 2 cycles using RECIST. Results: Median age= 58 years and 77% of pts had >2 prior chemotherapies for MBC. Initially 2 of 2 pts treated (D= 75 mg/m2, E= 30 mg) developed DLT (neutropenic fever/infection), prompting a mandatory PK evaluation for all pts enrolled in subsequent cohorts. A second cohort of 3 patients (D=60 mg/m2, E=20mg) had no DLT, but no pts received day 8 of E due to grade 3–4 neutropenia. PK analyses demonstrated a 42% lowered (-42%) D clearance at the 60 mg/m2 in the presence of E (n=1). Subsequent cohorts were accrued at D=40 mg/m2 with escalating doses of E (Table). For the entire group, an 18% decrease (-18%) in D clearance was observed when D was administered concomitantly with E. High interpatient variability of D clearance was observed (range +16% to -135%). No pts had CR/PR, but 6 had SD>4 cycles and 2 had SD=8 cycles. Conclusions: Weekly everolimus appears to cause widely variable and unpredictable changes in docetaxel clearance making this combination unfeasible. [Table: see text] No significant financial relationships to disclose.

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