A Phase I/II Trial on Melphalan, Prednisone, Thalidomide and Defribotide Combination in Relapsed/Refractory Multiple Myeloma Patients.

Abstract Defibrotide (DF) showed antithrombotic properties and remarkable activity in Multiple Myeloma (MM), without significant anticoagulant effects and bleeding risk. DF may abrogate tumor cells interaction with marrow stromal cells and enhance sensitivity to chemotherapy, thus improving activities of Melphalan, Prednisone and Thalidomide, while protecting against thrombotic state. We designed a multicenter phase I/II trial to define efficacy and safety of Melphalan, Prednisone, Thalidomide and DF (MPTD) in relapsed/refractory MM. The MPTD treatment consisted of 6 35-days cycles of oral melphalan (0.25 mg/Kg day 1–4), prednisone (1.5 mg/kg day 1–4), thalidomide (50–100 mg/day continuously), DF at 3 dose levels (17 mg/Kg iv or 2.4 g po D 1–4, 1.6 g po D 5–35; 34 mg/Kg iv or 4.8 g po D 1–4, 3.2 g po D 5–35; 51 mg/Kg iv or 7.2 g po D 1–4, 4.8 g po D 5–35), every 35 days, without deep vein thrombosis (DVT) prophylaxis. Safety was assessed by defining dose-limiting toxicity (DLT) and maximum tolerated dose (MTD). DLT was defined as the occurrence of febrile neutropenia, G4 neutropenia >1 week, any other G4 hematologic toxicity, or any >G3 non-hematologic toxicity. MTD was the dose level prior to that resulting in DLT. Efficacy was evaluated according to EBMT/IBMTR criteria. Twenty-four patients were enrolled between March and November 2006 and 19 patients completed at least 1 MPTD (median age 69, excluding primary refractory and/or patients receiving anticoagulation) and were evaluated for toxicity and response. Fourty-two percent of patients achieved at least partial response (PR) after a median of 3 cycles (including 16% very good PR), without significant differences among DF dose. The MTD was not reached. DLTs observed were not considered related to DF and included: G3 ileus (1st dose level) and acute myocardial infarction (AMI) in the 2nd. Toxicities ≥G3 consisted of neutropenia 47%, thrombocytopenia 10%, anemia 21%, whereas <5% of patients experienced non-hematological toxicities ≥G3. No DVTs or significant bleeding were detected. Treatment discontinuation occurred in 3 patients for adverse events: AMI (additional anticoagulation required), ileus (because of the diagnosis of amyloidosis AL and disease progression), and persistent G4 neutropenia (heavily pre-treated patients). In this phase I/II study we confirm the efficacy and feasibility of MPTD in the setting of advanced myeloma patients, interestingly a protective role of DF against thrombosis is also suggested. Pharmacokinetic studies and analysis of surrogates are ongoing. Updated data will be presented at the meeting.

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A Phase I–II Trial of Bortezomib (Velcade) (Vc) and Oral Cyclophosphamide (CY) Plus Prednisone (P) for Relapsed/Refractory Multiple Myeloma (MM).

Blood ◽

10.1182/blood.v106.11.2556.2556 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2556-2556 ◽

Cited By ~ 8

Author(s):

Donna E. Reece ◽

Giovanni Piza ◽

Suzanne Trudel ◽

Christine Chen ◽

Joseph R. Mikhael ◽

...

Keyword(s):

Phase I ◽

Dose Level ◽

Progression Free Survival ◽

Maximum Tolerated Dose ◽

Hematologic Toxicity ◽

Combination Regimen ◽

Free Survival ◽

Best Response ◽

Level 3 ◽

Ongoing Phase

Abstract We have previously reported that a simple, well-tolerated regimen of weekly oral CY (500mg) and alternate day prednisone (50–100mg) produced partial responses (PR) in 40% of 56 patients (pts) in relapse after ASCT; median progression-free survival was 18.6 months (Blood2004; 104[11]: 311b). To build upon these favorable results, we have designed an ongoing phase I–II trial adding Vc to this regimen. CY was given p.o. once weekly on days 1,8,15 and 22 of each 28 day cycle while prednisone was given every other morning. CY was given before Vc on appropriate days. A maximum of 8 cycles was administered. Sixteen pts have been entered so far. Patients characteristics: Median age was 59 (48–74) years; 9 were male. The Ig subtypes were: IgG kappa:lambda = 9:2, IgA kappa:lambda = 1:2; kappa light chain = 2. All had received VAD, i.v. CY (2.5 g/m2) + G-CSF mobilization followed by ASCT and 2 had undergone a second ASCT; other prior regimens included melphalan and prednisone in 5 pts, thalidomide in 10, lenalidomide in 1, α-interferon in 3, vaccine therapy in 1 and oral CY + P in 8. The median pretreament ß2-microglobulin level was 279 (147 – 875) nm/L, albumin 39 (30–42) g/L and creatinine 91 (60–112) umol/L. The dose escalation schedule to date is as follows: Dose Level N P dose CY dose (mg/m2) Vc dose (mg/m2) 1 6 100 150 0.7 d 1,8,15 2 3 100 300 0.7 d 1,8,15 3 3 100 300 1.0 d 1,8,15 4 4 100 300 1.0 d 1,4,8,11 Three further dose escalations to a maximum Vc dose of 1.5 mg/m2 days 1,8, and 15 are allowed if dose limiting toxicity does not occur. Toxicities during cycle 1: All pts have completed cycle 1. Three episodes of grade (gr) 3 sinopulmonary infection occurred during a community outbreak at dose level 1; levofloxacin prophylaxis during the first cycle was added and no further infections during the initial cycle were observed. One pt at dose level 3 experienced transient gr 4 hypophosphatemia which reversed without therapy. At dose level 4, cycle 1 was interrupted in one pt due to gr 4 leukopenia (gr 3 neutropenia and thrombocytopenia) related to disease, while a second pt developed grade 4 elevation in transaminases which recovered quickly when Vc was held on d 8. Pt accrual continues. Toxicities of subsequent cycles: To date, 47 additional cycles have been given. SAE’s consisted of pneumonia during cycle 2 in the same 3 patients with infection during cycle 1 and one of these with progressive disease had another bout during cycle 3. Gr 3 toxicities included anemia in 2 cycles, leucopenia in 2, neutropenia in 4, hypophosphatemia in 1 and hyperglycemia in 2; reversible gr 4 hypophosphatemia recurred in the pt mentioned above in 1 other cycle. No liver or other organ toxicity was observed. Maximum gr of peripheral neuropathy was 1. Responses: Responses were assessed after cycles 2, 4, 6 and 8. Best response included near CR (1), PR (4), MR (4), stable disease (5), progression (1) and too early (1). Two pts have completed all 8 cycles, while 4 have progressed; 10 remain on study. Preliminary Conclusions: 1) Vc can be added to a continuous program of oral CY + P with acceptable hematologic toxicity; 2) no neurotoxicity > gr 1 has been observed; 3) the maximum tolerated dose (MTD) of this combination regimen has not yet been defined; 4) future plans include a randomized National Cancer Institute of Canada trial comparing the the MTD of this combination to Vc in relpased MM pts.

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Phase I Study of Triapine® and Cytarabine (ara-C) in Patients with Relapsed or Refractory Acute Leukemias and High-Risk Myelodysplastic Syndrome (MDS).

Blood ◽

10.1182/blood.v106.11.4925.4925 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4925-4925

Author(s):

Karen W.L. Yee ◽

Jorge Cortes ◽

Guillermo Garcia-Manero ◽

Srdan Verstovsek ◽

Alessandra Ferrajoli ◽

...

Keyword(s):

High Risk ◽

Phase I ◽

Dose Level ◽

Phase I Study ◽

Maximum Tolerated Dose ◽

Hematologic Toxicity ◽

Cell Transplant ◽

Acute Leukemias ◽

Elevated Liver Enzymes ◽

Synergistic Cytotoxicity

Abstract Triapine is a potent inhibitor of ribonucleotide reductase (RNR), which is required for the conversion of ribonucleotides to deoxyribonucleotides. Two phase I trials in patients with hematologic malignancies demonstrated that Triapine could reduce circulating blasts in the majority of patients without significant non-hematologic toxicity (Giles et al. Leuk Res2003;27:1077–1083; Karp et al. Blood2002;100:560a). Preclinical studies have shown that the combination of Triapine and ara-C produces additive or synergistic cytotoxicity against several tumor cell lines, potentially by increasing intracellular ara-CTP levels when Triapine inhibits RNR. Therefore, a phase I study of Triapine in combination with ara-C was conducted in 32 patients with relapsed or refractory acute leukemia and high-risk MDS (1 MDS, 28 AML, 2 Ph+ ALL, and 1 Ph- ALL) in order to determine the tolerability, safety, and maximum tolerated dose (MTD). Triapine® was administered at a dose of 105 mg/m2/d as a 6-hour infusion for 5 consecutive days (D1–5) followed immediately by ara-C [100 (n=4), 200 (n=6), 400 (n=7), or 800 (n=8) mg/m2/d] as an 18-hour infusion for 5 consecutive days (D1–5). Median age was 59 years (range, 15–83 years). Median ECOG status 1 (range, 0–2). Median number of prior therapies was 2 (range 1–9), including prior autologous (n= 2) and allogeneic stem cell transplant (SCT) (n=4). Dose-limiting toxicities (DLTs) were observed at the 800 mg/m2 ara-C dose level (1 patient each with grade 4 mucositis; grade 4 neutropenic colitis, sepsis and death; grade 4 neuropathy; and grade 4 hyperbilirubinemia). Therefore, the study was amended to include an ara-C dose level of 600 mg/m2/d. Seven patients were treated at this dose level without development DLTs. Thirty-one patients received at least 1 course, 2 received 2 courses, and 4 received 3 courses; 1 patient withdrew prior to completion of 1 course of therapy. Of the 31 evaluable patients, 4 (13%) patients (3 AML, 1 Ph+ ALL) achieved a CR (1 at an ara-C dose of 800 mg/m2; 2 at 600 mg/m2; 1 at 200 mg/m2). Two of the responders also achieved a complete cytogenetic remission (including 1 Ph+ ALL). All responses occurred after 1 induction course. One patient went on to receive an allogeneic (SCT) and continues in CR. Duration of responses was 9, 20, 52+, and 73+ weeks. Mean Cmax and AUC achieved for Triapine were 1.13 μg/mL and 251.5 min•μg/mL. The most frequent toxicities included nausea &/or vomiting (66%), elevated liver enzymes (50%; gr. 3 in 22%), fever (47%), diarrhea (41%; gr. 3 in 6%), rash (31%; gr. 3 in 6%), mucositis (28%), hand-foot syndrome (16%; gr. 3 in 3%), and peripheral edema (16%; gr. 3 in 9%). Triapine and cytarabine has activity in patients with relapsed or refractory acute leukemias. The recommended phase II dose is Triapine 105 mg/m2/day for 5 consecutive days (D1–5) followed by ara-C 600 mg/m2/d for 5 consecutive days (D1–5).

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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 Clinical Trial of Oral Administration of the Histone Deacetylase (HDAC) Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) in Patients with Relapsed/Refractory Multiple Myeloma (MM).

Blood ◽

10.1182/blood.v104.11.1503.1503 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1503-1503 ◽

Cited By ~ 8

Author(s):

Paul Richardson ◽

Robert L. Schlossman ◽

Constantine S. Mitsiades ◽

Nikhil C. Munshi ◽

Kathleen Colson ◽

...

Keyword(s):

Clinical Trial ◽

Multiple Myeloma ◽

Phase I ◽

Dose Level ◽

Hdac Inhibitor ◽

Hydroxamic Acid ◽

Phase I Clinical Trial ◽

Hematologic Toxicity ◽

Suberoylanilide Hydroxamic Acid ◽

Grade 3

Abstract Introduction: Histone deacetylases (HDACs) affect cell growth at the transcriptional level by regulating the acetylation status of nucleosomal histones, and HDAC inhibition induces differentiation and/or apoptosis in transformed cells. We have recently shown that HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA), induce apoptosis of human multiple myeloma (MM) cells via a constellation of antiproliferative and/or proapoptotic molecular events, including decreased expression of multiple signaling molecules and oncogenes implicated in MM pathophysiology. Based on these promising pre-clinical data, we embarked on a phase I clinical trial of oral SAHA in patients with advanced MM. Methods: An open-label phase I dose-escalation of oral SAHA (200, 250 and 300 mg po bid for 5 consecutive days followed by 2 days of rest) was administered in 4-week cycles in pts with relapsed/refractory MM. The primary objective was to determine the maximum tolerated dose (MTD), and secondary objectives included evaluation of tumor response, as well as assessment of markers of biologic activity in peripheral blood mononuclear cells and bone marrow plasma cells. Dose limiting toxicity (DLT) was defined as grade 4 or greater hematologic toxicity and/or grade 3 or greater non-hematologic toxicity within the first 28 days of treatment. Results: To date, 8 pts with advanced MM (5 relapsed and 3 with relapsed, refractory MM) have been enrolled at the first 2 dose levels, receiving a median of 3 cycles (range 2–9) of therapy. In 7 evaluable pts, one pt at the 2nd dose level (250 mg po bid) developed DLT with grade 3 fatigue, prompting dose reduction with the next cycle. Other side effects have included grade 2 fatigue (3 pts), grade 2 diarrhea (2 pts), grade 2 indigestion (2 pts) and grade 2 dehydration (2 pts), which have been manageable with appropriate supportive care. In one patient, during cycle 4 at dose level 2, grade 3 dehydration occurred with associated metabolic abnormalities that readily resolved with electrolyte supplementation and rehydration. The patient has continued on therapy at reduced dose (250 mg po bid, 4 days on, 3 days off) without recurrence of this toxicity. Importantly, no significant myelosuppression, neuropathy or sedation, which are associated with other anti-MM agents, has been seen. In 7 evaluable pts: minor responses (MR) were documented in 2 patients (25–50% reduction in serum paraprotein levels); stable disease (SD: less than 25% reduction in paraprotein levels) was observed in 2 pts; and progressive disease (PD) was documented in 3 pts. Conclusion: SAHA is an orally administered HDAC inhibitor with manageable toxicity and preliminary evidence of antitumor activity in advanced MM. Clinical evaluation of this agent continues, with enrolment at 250 mg b.i.d. ongoing, to further define the safety and tolerability at this dose level and provide insight into the future uses of SAHA, either alone or in combination with other agents, to treat pts with advanced MM.

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Phase I Trial of Rituximab, Cladribine and Temsirolimus (RCT) for Initial Therapy of Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v120.21.3661.3661 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3661-3661 ◽

Cited By ~ 1

Author(s):

David J. Inwards ◽

Paul Fishkin ◽

Betsy R. LaPlant ◽

Matthew T. Drake ◽

Paul Kurtin ◽

...

Keyword(s):

Adverse Events ◽

Phase I ◽

Mantle Cell Lymphoma ◽

Dose Level ◽

Cell Lymphoma ◽

Maximum Tolerated Dose ◽

Hematologic Toxicity ◽

Mantle Cell ◽

Grade 3 ◽

Dose Levels

Abstract Abstract 3661 Objective: We conducted this trial to determine the maximum tolerated dose (MTD) and schedule of temsirolimus added to an established regimen comprised of rituximab and cladribine for the initial treatment of mantle cell lymphoma and to generate preliminary information on the toxicity and efficacy of this combination. Methods: A standard phase I cohort of 3 study design was utilized. MTD was defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum of 6 new patients). DLT was defined as grade 4 ANC (<500) for ≥5 days, grade 4 ANC (<500) associated with fever (>100.5 F) and/or active infection, PLT <25,000, grade 4 infection, or ≥grade 3 non-hematologic toxicity during the first cycle of therapy as per NCI Common Terminology Criteria for Adverse Events v3.0. The fixed doses of rituximab and cladribine were 375 mg/m2 IV day 1 and 5 mg/m2/d IV days 1–5 of a 28 day cycle, respectively, as previously published. There were 5 planned temsirolimus IV dose levels: 15 mg day 1; 25 mg day 1; 25 mg days 1 and 15; 25 mg days 1,8 and 15; and 25 mg days 1,8,15, and 22. The fifth dose level is as previously published in combination with rituximab. Results: A total of 17 patients were treated: 3 each at dose levels 1–4 and 5 at dose level 5 (25 mg temsirolimus days 1,8,15, and 22). The median age was 75 years (52–86). There were 11 males and 6 females. At presentation 88% had stage IV disease, and 94% had extranodal disease. MIPI scores were low in 6% (1 patient), intermediate in 59% (10 patients), and high in 35% (6 patients). There was a single DLT recorded at dose level 3 based on the initial DLT criteria, though this cytokine release syndrome was clearly rituximab related, and occurred prior to the first dose of temsirolimus. Five patients were treated at the highest planned temsirolimus dose level (25 mg days 1,8,15, and 22) with no DLT observed. No further dose escalation was planned, and this level was determined to be tolerated, though higher levels may be tolerable. All patients were evaluable for adverse events. Hematologic toxicity was frequent, with grade 3 anemia in 12% of patients, grade 3 thrombocytopenia in 35%, grade 4 thrombocytopenia in 30%, grade 4 lymphopenia in 47%, grade 3 neutropenia in 24%, and grade 4 neutropenia in 18% of patients. There were 3 thrombotic episodes, 2 of which were attributed to therapy, and 3 episodes of pneumonitis. The overall response rate was 94% with 53% CR and 41% PR. The median progression free survival was 18.7 months. Conclusions: Temsirolimus 25 mg IV weekly may be safely added to rituximab and cladribine at 375 mg/m2 IV day 1 and 5 mg/m2/d IV days 1–5 of a 28 day cycle, respectively. This regimen had promising preliminary activity in an elderly cohort of patients with mantle cell lymphoma. Disclosures: Off Label Use: Temsirolimus for mantle cell lymphoma.

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Phase I trial of bevacizumab plus sunitinib in patients (pts) with metastatic renal cell carcinoma (mRCC)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.5099 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 5099-5099 ◽

Cited By ~ 17

Author(s):

D. R. Feldman ◽

G. V. Kondagunta ◽

E. A. Ronnen ◽

P. Fischer ◽

R. Chang ◽

...

Keyword(s):

Phase I ◽

Dose Level ◽

Phase I Trial ◽

Kinase Inhibitor ◽

Maximum Tolerated Dose ◽

Fixed Dose ◽

Rapid Progression ◽

Hematologic Toxicity ◽

Phase Ii Trials ◽

Dose Levels

5099 Background: Bevacizumab, an intravenous monoclonal antibody against VEGF, and sunitinib, an oral multi-targeted tyrosine kinase inhibitor of VEGF and PDGF receptors, both have activity in mRCC [NEJM 349:427–434; JAMA 295:2516–2524]. Combining bevacizumab and sunitinib may increase antitumor efficacy by maximizing inhibition of the VEGF pathway. The safety and maximum tolerated dose (MTD) of sunitinib in combination with bevacizumab was assessed in this Phase I trial. Methods: Cohorts of 3–6 pts with mRCC received escalating doses of sunitinib (dose levels: 25, 37.5, and 50 mg po) daily for 4 weeks (wks) followed by 2 wks off with fixed- dose bevacizumab (10 mg/kg iv) every 2 wks continuously. Pre-determined dose-limiting toxicities (DLTs) in the first 6-wk cycle included Grade (Gr) 4 neutropenia, ≥Gr 3 thrombocytopenia of ≥7 days, Gr 4 hypertension or proteinuria, and other Gr 3 non-hematologic toxicity of ≥7 days. Pts who came off study prior to completion of cycle 1 for any reason other than a DLT were replaced. Serum VEGF levels were measured before and during cycles 1 and 2. Results: 16 pts (11 male, 5 female, median age 57) were enrolled. Of 8 patients entered at the first dose level (sunitinib 25 mg, bevacizumab 10 mg/kg), 2 were replaced; 1 never received treatment and 1 did not complete cycle 1 due to rapid progression of disease (PD). No DLTs occurred in the remaining 6 evaluable pts in this cohort. At the 2nd dose level (n =6, sunitinib 37.5 mg, bevacizumab 10 mg/kg), 1 pt receiving low molecular weight heparin had a DLT of Gr 4 hemorrhage. 2 pts have enrolled in the 3rd dose level (sunitinib 50 mg, bevacizumab 10 mg/kg) but are not yet evaluable for toxicity or response. Gr 3/4 toxicities over all cycles included Gr 3 hypertension (n=4), Gr 3 proteinuria (n=2), Gr 3 abdominal pain (n=2), Gr 4 hemorrhage (n=1), and Gr 3 hand/foot syndrome (n=1). 13 pts were evaluated for best response–4 had partial responses, 7 had stable disease, and 2 had PD. Serum VEGF levels decreased during cycle 1 in all pts. Conclusions: The combination of sunitinib and bevacizumab in mRCC pts was tolerable at the first 2 dose levels. Once the MTD is identified, further testing of this combination in phase II trials may be indicated for mRCC as well as other malignancies. [Table: see text]

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Phase I-II Trial of Bortezomib Plus Oral Cyclophosphamide and Prednisone in Relapsed and Refractory Multiple Myeloma

Journal of Clinical Oncology ◽

10.1200/jco.2007.14.2372 ◽

2008 ◽

Vol 26 (29) ◽

pp. 4777-4783 ◽

Cited By ~ 79

Author(s):

Donna E. Reece ◽

Giovanni Piza Rodriguez ◽

Christine Chen ◽

Suzanne Trudel ◽

Vishal Kukreti ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Dose Level ◽

Overall Response Rate ◽

Response Rate ◽

Maximum Tolerated Dose ◽

Oral Cyclophosphamide ◽

Refractory Multiple Myeloma ◽

Grade 3 ◽

Dose Levels

PurposeThe combination of oral weekly cyclophosphamide and alternate day prednisone is a convenient regimen for relapsed/refractory multiple myeloma (MM), and we sought to improve its efficacy by adding bortezomib, a proteasome inhibitor with proven antimyeloma activity.Patients and MethodsWe conducted a phase I-II trial evaluating six dose levels to define the maximum tolerated dose (MTD) of this combination in relapsed/refractory MM. An additional 10 patients were evaluated at the highest dose level reached.ResultsThirty-seven patients were treated on this study. The MTD was not defined. Both of the highest dose levels of bortezomib tested (1.3 mg/m2on days 1, 4, 8, and 11 and 1.5 mg/m2on days 1, 8, and 15, each on a 28-day cycle) could be safely given with cyclophosphamide 300 mg/m2per week and prednisone. At these dose levels, the overall response rate was 95% (complete responses [CR] plus partial response plus minimal response), with CR observed in more than 50% of patients. The weekly bortezomib regimen resulted in fewer instances of grade 3 thrombocytopenia and grade 1 to 2 peripheral neuropathy; the 1-year progression-free and overall survival probabilities with this dose level were 83% (95% CI, 73% to 96%) and 100%, respectively.ConclusionWeekly bortezomib 1.5 mg/m2plus oral cyclophosphamide and prednisone produces an unprecedented response rate and encouraging 1-year survival in relapsed/refractory patients with MM. Further evaluation of this promising regimen is warranted both in relapsed and newly diagnosed disease.

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A Phase I/II Study of Pomalidomide-Cyclophosphamide-Prednisone (PCP) in Patients with Multiple Myeloma Relapsed/Refractory to Lenalidomide

Blood ◽

10.1182/blood.v118.21.632.632 ◽

2011 ◽

Vol 118 (21) ◽

pp. 632-632 ◽

Cited By ~ 1

Author(s):

Antonio Palumbo ◽

Alessandra Larocca ◽

Angelo Michele Carella ◽

Davide Rossi ◽

Vittorio Montefusco ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Treatment Options ◽

Maximum Tolerated Dose ◽

Hematologic Toxicity ◽

Advisory Committees ◽

Grade 3

Abstract Abstract 632 Background: Patients with multiple myeloma (MM) relapsed/refractory after immunomodulatory drugs and bortezomib have limited treatment options. Recently, the combination pomalidomide-dexamethasone has led to at least partial response (PR) of 25–42% in relapsed/refractory MM and 32% in patients refractory to lenalidomide. Aims: In this study we evaluate the safety and efficacy of the combination pomalidomide-cyclophosphamide-prednisone (PCP) in patients with MM who received 1–3 lines of treatment and were relapsed/refractory to lenalidomide therapy. Methods: Between August 2010 and July 2011, 41 patients were enrolled; median age was 69 years (range 49–82); 23 patients relapsed after lenalidomide and 18 patients were refractory to lenalidomide. The first 24 patients entered the phase I of the study to define the maximum tolerated dose (MTD) of PCP: 4 dose levels of pomalidomide (1, 1.5, 2 and 2.5 mg/day, days 1–28) were tested in combination with cyclophosphamide (50 mg every other day, days 1–28) and prednisone (50 mg every other day, days 1–28) for six 28-day cycles. Thromboprophylaxis with aspirin (100 mg/day) was recommended, low-molecular weight heparin was given to high risk patients. Dose Limiting Toxicities (DLTs) were defined as: grade 4 neutropenia for more than 3 days, grade 4 thrombocytopenia, grade 3–4 neutropenic fever, any grade 3–4 non-hematologic toxicity. The MTD was achieved when 25% of patients experienced a DLT, using the Bayesian Continual Reassessment Method. In the phase II of the study, the Simon two-stage design was used and 17 additional patients were enrolled and received the MTD of pomalidomide. Results: DLTs occurred in 1/4 patient who received pomalidomide 1.5 mg (grade 4 thrombocytopenia) and in 3/12 patients who received pomalidomide 2.5 mg (grade 3 neuropathy, grade 3 hepatic toxicity and grade 4 thrombocytopenia). The MTD was defined at 2.5 mg/day, with an estimated DLT probability of 0.258 (95% credibility interval: 0.101–0.468). 32 patients received at least one cycle of therapy and could be evaluated for efficacy and safety. At least PR was reported in 19/32 (59%) patients, including 2 complete response (CR), 5 very good partial response (VGPR), 12 PR. In patients refractory to lenalidomide, at least PR was reported in 11/15 (73%) patients, including 1 CR, 2 VGPR, 8 PR. Grade 4 hematologic toxicities were neutropenia (9%) and thrombocytopenia (9%). Grade 3–4 non-hematologic toxicity included infection (9%), rash (9%), neurologic (6%) and hepatic (3%) toxicities. Thromboembolism occurred in 1 patient. Conclusions: At least PR was achieved in 73% of patients refractory to lenalidomide; grade 4 neutropenia and/or thrombocytopenia were less than 10%. The combination pomalidomide (2.5 mg/day), cyclophosphamide (50 mg every other day), prednisone (50 mg every other day) showed high response rates with limited toxicities in patients relapsed/refractory to lenalidomide. Updated data will be presented at the meeting. Disclosures: Palumbo: Amgen: Honoraria; Merck: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larocca:Janssen-Cilag: Honoraria. Guglielmelli:Janssen-Cilag: Honoraria; Celgene: Honoraria. Giuliani:Celgene: Research Funding; Novartis: Research Funding. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Phase I trial of bortezomib and celecoxib in patients with advanced solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.13051 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 13051-13051 ◽

Cited By ~ 1

Author(s):

S. Dunder ◽

U. B. Chaudhary ◽

M. Green ◽

M. Meyer ◽

F. Brescia ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Solid Tumors ◽

Renal Cell ◽

Treated Patient ◽

Cell Cancer ◽

Maximum Tolerated Dose ◽

Hematologic Toxicity ◽

Advanced Solid Tumors ◽

Cox 2

13051 Background: The ubiquitin-proteosome pathway plays an important role in cell cycle regulation, neoplastic growth, and metastasis. Nuclear factor-kB (NF-kB) is a key transcription factor in cancer, primarily regulated by proteosome-mediated degradation of the inhibitor protein I kappa B alpha-associated protein kinase (IkBa). Interruption of this degradative pathway, with the 26S proteosome inhibitor bortezomib, has displayed significant clinical anti-tumor activity, in multiple myeloma and lymphomas. The role of bortezomib in the treatment of advanced solid tumors, however, is unclear at present. Preclinical work in multiple myeloma cell lines has demonstrated synergy in cytotoxicity and growth inhibiton with the combination of bortezomib and the cyclooxygenase (COX)-2 inhibitors. We therefore hypothesized that the combination of the COX-2 inhibitor celecoxib and bortezomib is a potentially active combination in the treatment of advanced solid tumors. Towards this aim, we are conducting a phase I study to determine the maximum tolerated dose (MTD) and toxicity profile of bortezomib and celecoxib. Methods: Patients with advanced solid tumors and an ECOG PS of 0–2 received escalating doses of bortezomib (1.0–1.6 mg/m2), either weekly for 5 of 6 weeks or twice weekly for 2 of 3 weeks, and celecoxib (200–400 mg twice daily). Accrual was planned to a maximum of 6 cohorts, each with a minimum of 3 patients. Only those dose-limiting toxicities (DLTs) occurring during the first cycle were used to define the MTD. DLTs included any grade 4 hematologic toxicity related to therapy, or any grade 3 or 4 non-hematologic toxicity. Results: To date, 10 patients (median age of 63y) have been treated. Represented tumor types include stage IV: colorectal, pancreatic, bladder, leiomyosarcoma, head and neck squamous cell carcinoma, hepatocellular, and renal cell. A median number of 2 cycles were administered. Thus far, no DLTs have been observed. No cumulative toxicities have been noted. No objective tumor response has been observed, however, stable disease was maintained in one heavily pre-treated patient with metastatic papillary renal cell cancer for 5 months. Conclusions: The combination of bortezomib and celecoxib is safe and well tolerated, with no dose-limiting toxicities thus far. [Table: see text]

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Preliminary results of a phase I trial of sorafenib combined with cisplatin/etoposide (CE) or carboplatin/pemetrexed (CbP) in solid tumor patients (pts)

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e13521 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e13521-e13521

Author(s):

N. S. Dhruva ◽

T. E. Stinchcombe ◽

C. M. Walko ◽

M. A. Socinski ◽

S. Bernard ◽

...

Keyword(s):

Febrile Neutropenia ◽

Phase I ◽

Dose Level ◽

Phase I Trial ◽

Single Agent ◽

Median Number ◽

Maximum Tolerated Dose ◽

Small Cell ◽

Hematologic Toxicity ◽

Level 1

e13521 Background: Sorafenib had demonstrated single agent activity in non-small cell and small cell lung cancer. Methods: A non-comparative, two arm phase I trial escalating sorafenib in combination with fixed doses of CE or CbP was performed. A 3-patient cohort design was utilized to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT). Dose level 0 for all pts was a sorafenib dose of 200 mg po BID continuously. Pts on arm A received C (60 mg/m2) on day 1 and E 120 mg/m2 on days 1,2,3 every 3 weeks with escalating doses of sorafenib. On arm B, pts received treatment with Cb (AUC=6) and P 500 mg/m2 every 3 weeks with escalating doses of sorafenib. However, excessive toxicity was observed on arm B, therefore the trial was amended such that Cb dose was lowered to AUC=5 (arm C). DLT were assessed in the 1st cycle and defined as grade (gr.) 4 anemia or thrombocytopenia, gr. 4 neutropenia lasting > 7 days, gr. ≥ 3 non-hematologic toxicity (except nausea, vomiting, and alopecia) and > 2 week dose delay. Response was assessed every 2 cycles according to RECIST, and best response was recorded. Results: Between 9/2007 and 9/2008, 20 pts were treated on the trial; median age 62 (range 47–73), male/female: 12/8, PS of 0/1: 6/14, and median number of prior therapies 2 (range 1–4). The most common tumor types were NSCLC (n=8), SCLC (n=4) and head/neck (n=2). At dose level 0 arm A (200 mg BID), 2 of 4 patients experienced DLT (gr.4 thrombocytopenia, gr.3 fatigue, febrile neutropenia and gr.4 neutropenia for > 7 days, gr.3 febrile neutropenia, diarrhea, hypokalemia, hyponatremia); 2 pts have been enrolled at dose level -1 (200 mg po QD) without DLT. Two of 3 patients enrolled on arm B at dose level 0 had gr.4 thrombocytopenia. On arm C at dose level 0 (200 mg po BID), 1/6 pts experienced DLT (gr.3 hyponatremia, dehydration, hypoglycemia). Enrollment continued at dose level 1 (400 mg po BID), but 2/5 pts experienced a DLT (both gr. 3 fatigue/anorexia). Responses observed were: PR (n=3) (all arm C), and SD (n=6). Conclusions: The MTD of sorafenib in combination with carboplatin (AUC=5) and pemetrexed 500 mg every 3 weeks is 200 mg po BID. The MTD of sorafenib in combination with cisplatin/etoposide has yet to be determined and is currently accruing at dose level -1. [Table: see text]

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