A Phase I Study of Cloretazine® and Temozolomide in Patients with Hematologic Malignancies.

Abstract Background: In recent single agent Phase I trials, both Cloretazine® (VNP40101M) and temozolomide (TMZ) have shown activity in relapsed leukemia with minimal non-hematologic toxicity (Giles et al, 2004, Seiter et al, 2002). The cytotoxic activity of Cloretazine and TMZ have been attributed to the alkylation at the O6 position of guanine leading to a futile cycle of misincorporation of thymidine and ineffective mismatch repair. In addition, activation of Cloretazine generates different alkylating and isocyanate species that produce DNA cross linkages leading to DNA strand breaks and apoptosis. Repair of Cloretazine and TMZ induced alkylation lesions have been attributed to the expression and irreversible activity of enzyme O6 alkylguanine DNA alkyltranferase (AGT). It has been shown that TMZ administered to patients once or twice daily can reduce AGT levels in tumor cells; therefore depletion of AGT by TMZ may sensitize cells to Cloretazine and result in synergistic anti-tumor activity. Methods: Cloretazine given after TMZ priming is currently evaluated in a Phase I dose escalation study. Patients are eligible if they have relapsed or refractory leukemia (ECOG 0–2). TMZ was given orally starting at a dose of 200 mg twice daily for 5 doses. Cloretazine is given intravenously on day 3, 2–4 hours after the last dose of TMZ starting at 100 mg/m2. Dose escalation of TMZ was guided by AGT depletion in leukemic blasts assessed by enzyme assay and HPLC (Gerson et al, 1985). Leukemia response is assessed according for standard criteria for CR and CRp (Cheson et al, 2003). Results: Thirty-two patients have been treated in the first 5 cohorts (I: 200mg TMZ +100mg/m2 Cloretazine n=7, II: 300mg TMZ+100mg/m2 Cloretazine n=6, III: 300mg TMZ + 200mg/m2 Cloretazine n=3, IV: 300 mg TMZ + 300mg/m2 Cloretazine n=7, V: 300 mg TMZ + 400mg/m2 Cloretazine n=9). Median age of the patients is 62 years (range 27–80), M:F = 20:12. Treatment with 300mg TMZ x 5 doses resulted in >90% depletion of AGT levels in 5 of 6 patients in cohort II and was fixed for subsequent dose escalation with Cloretazine. Myelosuppression was the most frequent adverse event occurring in 10/32 (30%) of treated patients (6 Grade 3–4 neutropenia, 4 Grade 3–4 thrombocytopenia). Non-hematologic toxicity has been minimal. To date, two patients treated with TMZ 300mg x 5 and Cloretazine 400 mg/m2 have experienced dose-limiting toxicity: Grade 3 pulmonary hemorrhage and Grade 3 neutropenic colitis in Cohort V and no unexpected toxicities were observed. Three early deaths occurred within 30 days (9.4%), all attributed to progressive disease. Responses are as follows: CR=3, CRp=1, and HI=2 for an overall response rate of 18.8%. The study is ongoing. Conclusions: Cloretazine® in combination with TMZ is tolerable and manageable. Evidence of anti-tumor effect has already been observed suggesting the combination of Cloretazine® and TMZ may potentiate their antileukemic activity.

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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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A Phase I Dose Escalation Study of PT-112 in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2020-134916 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 9-10

Author(s):

Taxiarchis Kourelis ◽

Sikander Ailawadhi ◽

Dan T. Vogl ◽

Dennis Cooper ◽

Tyler D Ames ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Dose Escalation ◽

Research Funding ◽

Single Agent ◽

Private Company ◽

Dose Escalation Study ◽

Refractory Multiple Myeloma ◽

Car T ◽

Grade 3

Background: PT-112 is a novel pyrophosphate-platinum conjugate with a multi-modal mechanism of action that induces immunogenic cell death and is not susceptible to DNA-repair drug resistance pathways. In phase I studies in solid tumors, PT-112 demonstrated safety and efficacy as single agent and in combination with PD-L1 checkpoint inhibitor avelumab, crossing a range of dose levels (DL) and tumor types, including in heavily pre-treated patients (pts) non-responsive to immunotherapy and refractory to other modalities. Non-clinical, in vivo research using advanced imaging technology demonstrated that PT-112 reached the highest concentrations in bone tissue (osteotropism). Moreover, PT-112 was highly active in the orthotopic, immune-competent Vk*MYC mouse model of multiple myeloma, including drug-resistant transplant variants. Thus, a rationale for PT-112 as an investigational candidate in multiple myeloma was established. Here, we present results of a phase I dose escalation study of PT-112 in pts with relapsed or refractory multiple myeloma (RRMM). Methods: A 3+3 design was used to determine the recommended phase 2 dose (RP2D) for PT-112 (28-day cycle IV days 1, 8, 15) in pts with evaluable RRMM who had exhausted available therapies (Tx), with adequate bone marrow (abs neutrophil count ≥ 1.0 x 109/L; platelet count ≥ 50 x 109/L; and hemoglobin ≥ 8.0 g/dL) and renal function (calculated creatinine clearance ≥ 30 mL/min), and ECOG PS 0-2. Results: A total of 24 pts were treated with PT-112 monotherapy across 6 DLs: 125 mg/m2, 3 pts; 180 mg/m2, 4 pts; 250 mg/m2, 5 pts; 300 mg/m2, 4 pts; 360 mg/m2, 4 pts; 420 mg/m2, 4 pts. Patients had a median age of 72 years and were heavily pre-treated, with a median of 8 prior lines of systemic Tx: 22 (92%) pts were triple-class refractory with 19 (79%) pts penta-refractory, and 3 (13%) pts refractory to BCMA-based therapies. The most common treatment-related adverse events (TRAEs) were thrombocytopenia (58%), neutropenia (42%), diarrhea (38%), and nausea (38%). 38% of pts had ≥1 grade 3 non-hematologic TRAE, with no grade 4 non-hematologic TRAEs reported. One dose-limiting toxicity (DLT) of grade 4 neutropenia occurred at the 420 mg/m2 DL. In addition, due to frequent dose reductions and modifications at this DL, the safety committee declared 360 mg/m2 as the RP2D. Among 8 patients who received a starting dose at / above the RP2D, 2 had stable disease and 4 experienced responses to PT-112 Tx. These included a confirmed partial response (PR) achieved in a 79-year-old pt with kappa free light chain (FLC) disease treated at 360 mg/m2, whose previous Tx included combination regimens with most approved therapies (penta-refractory) and stem cell transplantation. FLC levels declined by 65% from baseline on PT-112 therapy and the pt remained progression free for 4.5 months. A 72-year-old pt treated at the 420 mg/m2 DL, reduced to 250mg/m2 every other week over the course of Tx due to grade 3-4 cytopenias, had a confirmed minor response. Prior Tx with multiple lines given over 9 years included stem cell transplantation, most approved therapies (penta-refractory), prior investigational antibody and CAR-T cell Tx (primary refractory to CAR-T). The patient was M-protein negative, kappa FLC levels declined by 32% following the first dose reduction, and the pt remained progression free and clinically stable without complaints for 4.5 months. Additionally, two transient, unconfirmed PRs occurred in patients at the 420mg/m2 DL: in a triple-class-refractory 82-year-old previously treated with 5 lines of Tx, with 70% reduction in kappa FLC during cycle 1; and in a penta-refractory 85-year-old, who experienced disappearance of M-protein during cycle 1 and Gr 4 neutropenia (DLT). Conclusions: PT-112 monotherapy was feasible and well tolerated in this heavily pre-treated, multi-refractory multiple myeloma population, and the Phase I clinical data appear to validate the developmental hypothesis, built upon activity in the Vk*MYC mouse model of multiple myeloma. Responses were confirmed in 25% of patients treated at / above the RP2D using single-agent PT-112, an encouraging result in a dose escalation trial conducted in heavily refractory patients. Activity of PT-112 in RRMM patients may be explained by its osteotropism and its unique mechanism of action compared to other drug classes used to treat this disease. Further clinical study of PT-112 in RRMM is warranted in a phase 2 clinical trial. Disclosures Ailawadhi: Celgene: Honoraria; Janssen: Research Funding; Pharmacyclics: Research Funding; Amgen: Research Funding; Medimmune: Research Funding; BMS: Research Funding; Cellectar: Research Funding; Phosplatin: Research Funding; Takeda: Honoraria. Vogl:Janssen: Consultancy; Celgene: Consultancy; MorphoSys: Consultancy; Takeda: Consultancy; Active Biotech: Consultancy, Research Funding; Oncopeptides: Consultancy; Karyopharm: Consultancy. Ames:Phosplatin Therapeutics: Current Employment, Current equity holder in private company. Yim:Phosplatin Therapeutics: Current Employment, Current equity holder in private company. Price:Phosplatin Therapeutics: Current Employment, Current equity holder in private company. Jimeno:Phosplatin Therapeutics: Current Employment, Current equity holder in private company.

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Phase I dose escalation study of bortezomib in combination with lenalidomide in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.6621 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 6621-6621

Author(s):

Philip C. Amrein ◽

Eyal C. Attar ◽

Amir Tahmasb Fathi ◽

Steven L McAfee ◽

Martha Wadleigh ◽

...

Keyword(s):

High Risk ◽

Phase I ◽

Dose Escalation ◽

Median Number ◽

Severe Neutropenia ◽

Clinical Activity ◽

Hematologic Toxicity ◽

Dose Escalation Study ◽

Grade 3 ◽

Number Of Cycles

6621 Background: Both bortezomib (Bz) and lenalidomide have clinical activity in patients with MDS and AML. We conducted a phase I dose escalation study to determine the maximal tolerated dose (MTD) of Bz in combination with lenalidomide. Methods: Patients with MDS (IPSS score ≥ 0.5 or therapy-related) received Bz by IV bolus on Days 1, 4, 8, and 11 and lenalidomide 10 mg/day PO on Days 1-21 in 28 day cycles for up to 9 cycles. Three doses of Bz were tested (0.7, 1.0, or 1.3 mg/m2). Cohorts consisted of 3-6 patients; the dose of Bz was escalated if there were < 2 dose limiting toxicities (DLTs). Growth factor support and transfusions were permitted. Dose limiting toxicities (DLTs) were assessed during the first cycle and were defined as severe neutropenia (absolute neutrophil count ≤ 250/ul), thrombocytopenia (platelet count < 10,000/ul), grade ≥ 2 neurotoxicity, or other grade ≥ 3 non-hematologic toxicity. Following determination of the MTD, enrollment opened to patients with relapsed and refractory AML and those with untreated high risk disease for whom induction therapy was not indicated. Responses were assessed by IWG 2006 criteria for MDS and IWG 2003 criteria for AML. Results: 23 patients (14 men) were enrolled; one patient was inevaluable due to disease progression prior to starting protocol therapy. The median age was 73 years (range 54-87). There was 1 DLT observed, neutropenia, in 6 patients treated with 1.0 mg/m2 Bz and no DLTs at 0.7 or 1.3 mg/m2. The median number of cycles was 2 (range 2-9). Grade ≥ 3 toxicities possibly attributable to the treatment at any dose level were: anemia (2), thrombocytopenia (10), leukopenia (3), infection (1), rash (2), dyspnea (1), dizziness (1), hypotension (1), pneumonia (2) and neuropathy (1). Among the 14 patients with MDS, 1 patient with RARS experienced a CR and 2 with RAEB-2 experienced marrow CR (mCR). Among the 8 patients with AML, there was 1 CR. Conclusions: The maximal tested dose of Bz (1.3 mg/m2) in combination with lenalidomide is safe. Responses were seen in MDS and high risk AML. Future testing of this regimen is planned.

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2-Chlorodeoxyadenosine dose escalation in nonhematologic malignancies.

Journal of Clinical Oncology ◽

10.1200/jco.1993.11.4.671 ◽

1993 ◽

Vol 11 (4) ◽

pp. 671-678 ◽

Cited By ~ 37

Author(s):

A Saven ◽

H Kawasaki ◽

C J Carrera ◽

T Waltz ◽

B Copeland ◽

...

Keyword(s):

Dose Escalation ◽

Intravenous Infusion ◽

Hematologic Malignancies ◽

Maximum Tolerated Dose ◽

Malignant Astrocytoma ◽

Dose Escalation Study ◽

Tissue Samples ◽

Grade 3 ◽

Higher Doses ◽

Experienced Grade

PURPOSE We performed a dose-escalation study of 2-chlorodeoxyadenosine (2-CdA) in solid tumors to determine the maximum-tolerated dose (MTD) and define its toxicity profile at higher doses. PATIENTS AND METHODS Twenty-one patients, seven with malignant astrocytoma, twelve with metastatic melanoma, and two with metastatic hypernephroma, were enrolled onto the study. Patients were entered onto cohorts that received 0.10, 0.15, or 0.20 mg/kg/d of 2-CdA by continuous intravenous infusion for 7 days every 28 days. 2-CdA levels were determined by radioimmunoassay. In tumor tissue samples, deoxycytidine kinase (dCK) levels were measured by both enzyme activity and immunoreactive protein analysis. RESULTS Of seven patients treated with 2-CdA at 0.1 mg/kg/d, one experienced grade 3 or 4 myelotoxicity. Of 11 patients treated at 0.15 mg/kg/d, four experienced myelotoxicity, two after a single course of 2-CdA. All three patients who received 2-CdA at 0.2 mg/kg/d experienced myelosuppression. Neurologic events occurred in two patients, both with malignant melanoma. Two of seven patients (28.6%) with astrocytomas obtained partial responses with a median duration of 8 months. 2-CdA penetrated the blood-brain barrier. An association was found between dCK levels as measured by enzymatic activity and immunoreactive proteins, but this did not correlate with 2-CdA tumor responsiveness. CONCLUSION The MTD for 2-CdA delivered as a 7-day intravenous infusion in patients with nonhematologic malignancies was determined to be 0.1 mg/kg/d, the same as the MTD for patients with hematologic malignancies. There was no clinical correlation with dCK expression and response to 2-CdA. The responses noted in patients with malignant astrocytoma warrant further phase II study.

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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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A Multicenter Phase I/II Dose Escalation Study of Lenalidomide in Combination with Melphalan and Dexamethasone in Subjects with Newly-Diagnosed Light-Chain (AL)-Amyloidosis.

Blood ◽

10.1182/blood.v112.11.1732.1732 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1732-1732

Author(s):

Philippe Moreau ◽

Arnaud Jaccard ◽

Lotfi Benboubker ◽

Bruno Royer ◽

Valerie Coiteux ◽

...

Keyword(s):

Phase I ◽

Dose Escalation ◽

Response Rate ◽

Standard Dose ◽

High Dose ◽

Al Amyloidosis ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Open Label ◽

Dose Escalation Study

Abstract A recent prospective randomized trial comparing standard-dose to high-dose melphalan in patients presenting with newly diagnosed AL-amyloidosis showed that oral melphalan-dexamethasone (M-dex) given monthly could be considered the current standard of care, with a median survival of 56 months (Jaccard, N Engl J Med 2007). The use of a combination of lenalidomide and dexamethasone has also been tested in patients with symptomatic AL-amyloidosis. The initial dose of lenalidomide at 25 mg/day was poorly tolerated. However, a 15 mg/day dose regimen was well tolerated and effective, with both hematologic and organ responses (Dispenzieri, Blood 2007 & Sanchorawala, Blood 2007). Combining M-dex with lenalidomide (M-dex-rev) could increase the response rate but the toxicity of this regimen is still unknown. Thus we have initiated a multicenter single-arm open-label phase I/II dose escalation study of lenalidomide administered in combination with M-dex. The primary endpoint was the incidence of dose limiting toxicities (DLT) during the first cycle of lenalidomide at a given dose level in order to determine the maximum tolerated dose (MTD). In addition to melphalan 0.18mg/kg/day from day 1–4 of each 28 day cycle and dexamethasone 40mg/day from day 1– 4 of each 28 day cycle, 3 cohorts of 3 subjects were successively exposed to escalating doses of lenalidomide (5, 10 and 15mg once daily on days 1–21 of a 28 day cycle). DLT was defined using National Cancer Institute (NCI) common toxicity criteria during the first 4 weeks of treatment (one cycle) as the following: at least grade 2 cardiac arrhythmia, at least grade 3 non hematologic toxicity, grade 4 neutropenia lasting >7 days or any other Grade 4 hematologic toxicity, or treatment delay due to toxicity that occurred during the first cycle. No DLT was observed among the first 3 patients treated at 5, 10 and 15 mg lenalidomide/day. 9 additional subjects will be enrolled at 15 mg/day to better define the safety profile and estimate the hematologic and organ response rate. Final results regarding both toxicity and efficacy will be presented during the meeting.

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Phase I dose escalation study of the anti-IGF-1R monoclonal antibody CP-751,871 in patients with refractory solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.3586 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 3586-3586 ◽

Cited By ~ 9

Author(s):

P. Haluska ◽

H. Shaw ◽

G. N. Batzel ◽

L. R. Molife ◽

A. A. Adjei ◽

...

Keyword(s):

Monoclonal Antibody ◽

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Receptor Internalization ◽

Pharmacokinetic Analysis ◽

Adrenocortical Cancer ◽

Dose Escalation Study ◽

Multiple Tumor ◽

Grade 3

3586 Background: The insulin-like growth factor 1 receptor (IGF-IR), a tyrosine kinase, and its ligands (IGF-I & -2) are upregulated in many human tumors (e.g., breast, prostate, colon and non-small cell lung cancer) and enhance proliferative and prosurvival signaling. Inhibition of IGF-IR activation in tumor models suppresses tumor growth and increases tumor sensitivity to chemotherapy, supporting the development of agents targeting IGF-IR. CP-751,871 is a potent, highly specific, fully humanized, monoclonal antibody that inhibits IGF-IR autophosphorylation and induces receptor internalization. Methods: A Phase I dose escalation study was initiated to define the safety and tolerability, and to characterize the pharmacokinetic properties of CP-751,871 in patients with advanced solid tumors refractory to standard therapies. Results: Following informed consent and screening, a total of 24 patients with refractory solid tumors (e.g. colorectal, NSCLC, sarcoma and prostate cancer; 1–6 previous regimens) were enrolled. Patients received 3 to 20 mg/kg of CP-751,871 by IV infusion on Day 1 of 3-week cycles in four dose-escalation cohorts of 3 patients. No dose limiting toxicities were identified and the maximum feasible dose (MFD) cohort of 20 mg/kg was extended with 12 additional patients. No higher than grade 3 CTCAE v3.0 toxicities, attributed to study drug, have been so far reported. Grade 3 toxicities, all reported in patients dosed with 20 mg/kg of CP-751,871, are increased GGT (4%) and fatigue (4%). Grade 2 toxicities include: anorexia (7%), diarrhea (7%), increased GGT (4%), hyperglycemia (4%), fatigue (4%), increased urinary frequency (4%), nausea (4%), increased ALT (4%) and increased AST (4%). Pharmacokinetic analysis is currently ongoing. No objective responses were observed. At the MFD, patients received a median of 4 cycles (1–16). Three patients were stable for > 6 months and one patient, currently at cycle 16, remains on study. An additional cohort of 12 adrenocortical cancer patients is under evaluation. Conclusions: These data indicate that CP-751,871 is safe and well tolerated. Due to its good safety profile, CP-751,871 may constitute a suitable targeted agent to use in combination with approved therapies in multiple tumor types. No significant financial relationships to disclose.

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A phase I dose escalation study of pemetrexed in patients with advanced head and neck squamous cell cancer (HNSCC)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.6055 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 6055-6055 ◽

Cited By ~ 1

Author(s):

P. H. Morrow ◽

B. S. Glisson ◽

L. E. Ginsberg ◽

S. M. Lippman ◽

M. S. Kies ◽

...

Keyword(s):

Phase I ◽

Dose Escalation ◽

Cell Cancer ◽

Maximum Tolerated Dose ◽

Vitamin Supplementation ◽

Dose Escalation Study ◽

Grade 3 ◽

Ecog Ps ◽

Dose Levels ◽

Neck Squamous Cell Cancer

6055 Background: Despite recent advances in therapy, patients (pts) with recurrent or metastatic HNSCC continue to demonstrate a poor median survival. In these pts, early trials with pemetrexed, a novel antimetabolite that acts upon several enzymes involved in pyrimidine and purine synthesis, have demonstrated promising efficacy and tolerability. Prior studies found that the administration of oral dexamethasone with pemetrexed reduced the incidence of skin rash. Later, vitamin supplementation (B12 and folic acid), given in addition to the dexamethasone, further diminished side effects. However, no trial has yet evaluated the appropriate steroid dose and its relation to the dosing of pemetrexed, in the setting of vitamin supplementation. We conducted a phase I trial to determine the maximum tolerated dose, toxicity, and preliminary efficacy of pemetrexed when given with different schedules of, or in the absence of, dexamethasone in pts with advanced HNSCC who had been treated with at least one or more chemotherapy regimens. Methods: Eligible pts had metastatic or recurrent HNSCC, prior treatment with one or more chemotherapy regimens, ECOG PS =2, and life expectancy >3 months. A conventional algorithm-based dose escalation design was applied, with three predefined dose levels (DL) of pemetrexed (500 mg/m2, 600 mg/m2, and 700 mg/m2) within each schedule of dexamethasone (none, 20 mg IV on day 1, and 4 mg orally bid for 3 days). Results: A total of 23 pts have been enrolled; 18 pts were evaluable. Median age was 57 years (range 47–82). Median ECOG PS was 1 (range 0–2), and 75% of pts were male. Number of prior chemotherapy regimens were as follows: 1 (40%), 2 (35%), 3 (15%), and 4 (10%). Preliminary data demonstrated only 2 treatment-related adverse events that were grade 3 or greater: anemia (DL1) and pneumonia (DL 1). In all, 13 pts have received pemetrexed with less than standard recommended dexamethasone dosing (none or IV), including 7 pts who received no dexamethasone. Of the 18 evaluable pts, 1 pt had a partial response and 2 pts had stable disease. Conclusions: This represents the first study that demonstrates that steroids may not be required as premedication with pemetrexed. Due to the limited toxicity observed, trial enrollment continues with dose escalation. [Table: see text]

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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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A phase I study to evaluate safety and antitumor activity of biweekly BMS-936558 (Anti-PD-1, MDX-1106/ONO-4538) in patients with RCC and other advanced refractory malignancies.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.7_suppl.331 ◽

2011 ◽

Vol 29 (7_suppl) ◽

pp. 331-331 ◽

Cited By ~ 15

Author(s):

D. F. McDermott ◽

C. G. Drake ◽

M. Sznol ◽

J. A. Sosman ◽

D. C. Smith ◽

...

Keyword(s):

Antitumor Activity ◽

Phase I ◽

Median Duration ◽

Dose Escalation ◽

Tumor Type ◽

Duration Of Treatment ◽

Open Label ◽

Cell Renal Cell Carcinoma ◽

Dose Escalation Study ◽

Grade 3

331 Background: Programmed death-1 (PD-1), a T-cell inhibitory receptor, may suppress antitumor immunity. BMS-936558, a fully human PD-1 blocking antibody, has shown antitumor activity and manageable toxicity after biweekly dosing (Sznol, ASCO 2010, #2506). This report provides an update on safety and antitumor activity with special emphasis on RCC. Methods: An open-label phase I dose escalation study of BMS-936558 was conducted in patients (pts) with treatment refractory metastatic clear-cell renal cell carcinoma (RCC), castrate-resistant prostate cancer (CRPC), melanoma (MEL), non-small cell lung cancer, or colorectal cancer (CRC). Dose escalation continued to 10 mg/kg when an expansion cohort for pts (16) with each tumor type was opened for additional safety and efficacy information. Tumor response (RECIST) was evaluated every 8 weeks. Clinically stable pts with early PD could continue until further PD or clinical deterioration. Results: 126 pts (18 RCC) were treated with 1, 3, or 10 mg/kg. MTD was not reached. Across all doses, the most common AEs (Any/grade 3-4) were fatigue (45.2%/6.3%) and diarrhea (30.2%/0.8%) while the most common drug-related AEs (Any/grade 3-4) were fatigue (20.6%/0.8%), rash (11.9%/0%), pruritus (11.3%/0%), and diarrhea (10.3%/0.8%). There was no apparent relationship between dose and frequency of AEs. One pt died with sepsis while being treated for drug-related grade 4 pneumonitis. The median number of prior treatment regimens in the RCC cohort was 2 (range 1-6). Of the 18 RCC pts, 16 were treated with 10 mg/kg. The median duration of treatment was 7.6+mo. ORR was 5/16 (31.2%) and SD>4mo was 6/16 (37.5%). The median duration of response was 4.0+ mo (3.7-7.4+ mo). Of the 2 RCC pts treated with 1 mg/kg, 1 obtained a CR (12+ mo) and 1 had SD (21+ mo). For evaluable CRPC pts, 1/15 pts (6.7%) obtained a PR (2+ mo) and 3/15 (20%) had SD>4mo. Conclusions: BMS-936558 administered biweekly is tolerable and has encouraging antitumor activity in a previously treated patients with RCC. Data on baseline characteristics, long-term toxicity and response duration will be updated at the meeting. [Table: see text]

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