Vincristine Sulfate Liposomes Injection (VSLI, Marqibo): Interim Results From a Phase I Study in Children and Adolescents with Refractory Cancer

Abstract Abstract 1497 Background: Vincristine is active in many pediatric cancers, but cumulative neuromuscular toxicity is often dose limiting and requires a maximum dose cap. Liposomal carriers are capable of increasing the therapeutic index of anticancer agents by altering pharmacokinetic behavior. Vincristine sulfate liposomes injection (VSLI, Marqibo®) is a novel preparation of standard vincristine encapsulated in sphingomyelin/cholesterol liposomes. Clinical trials have demonstrated safety, tolerability and activity in adults with leukemias, lymphomas and solid tumors. Pediatric experience with VSLI is limited. Design: This single center Phase I dose-escalation study is designed to determine the maximum tolerated dose (MTD) and to assess safety, pharmacokinetics and activity of VSLI in pediatric patients with relapsed/refractory cancer. Patients with active central nervous system disease or ≥grade 2 sensory or motor neuropathy are excluded. Dose escalation is per a standard 3 + 3 Phase I trial design with enrollment following a rolling 6 strategy. VSLI is administered IV over 60-minutes every 7 days (± 3 days) for 4 consecutive weeks for a 28-day treatment cycle (4 doses/cycle). Cycles may be delayed by up to 1 week for toxicity. Two dose levels have been tested to date: 1.75 mg/m2 and 2.25 mg/m2(adult MTD). No individual dose cap is employed. A validated HPLC tandem mass spectrometry assay was used to quantitate total (liposomal encapsulated and non-encapsulated) vincristine. Results: 9 patients have been treated (Table): 6 with acute lymphoblastic leukemia (ALL) and 3 with solid tumors. All patients were heavily pre-treated and 2 had prior stem cell transplants. 6 of 9 completed at least 1 cycle of therapy, with 1 each removed early for alternative therapy, complications of ALL, or dose-limiting toxicity (DLT). Most treatment-related adverse events were reversible grade 1 and 2 severity including hepatic transaminase elevation, parasthesia, low white blood cell count, neutropenia and fatigue. 2 patients evaluable for hematologic toxicity developed grade 4 neutropenia that spontaneously and rapidly resolved. No DLT occurred on dose level 1. Grade 4 aspartate aminotransferase elevation was observed in one patient at the second dose level and this dose level is being expanded. 1 patient treated at dose level 1 had dose de-escalation starting with Cycle 2 Dose 3 due to neuropathy. No patient was taken off study due to neurotoxicity. 7 of 9 patients received a VSLI dose that exceeded the 2 mg dose limit set for standard vincristine. 6 patients were evaluable for response: 1 had a complete remission (CR) (minimal residual disease negative by flow cytometry); 3 had stable disease (SD); and 2 had progressive disease (PD). First-dose pharmacokinetic analysis revealed wide interpatient variation (Table). The median (range) maximum concentrations (Cmax) of total vincristine (ng/ml) were 1,485 (845-2,120) and 2,450 (1,690-3,690) at dose levels 1 and 2 respectively. The median plasma half-life (T½) was 8.5 and 13.5 hours at dose levels 1 and 2 respectively (range 1.8 to 40.4 hours). Conclusions: VSLI appears to be safe, tolerable and demonstrates preliminary activity in pediatric patients with refractory ALL and solid tumors. The toxicity spectrum appears to be similar in children and adults. Clearance of total vincristine in our study is approximately 100-fold lower in comparison to administration of standard vincristine. VSLI allows for intensification of vincristine therapy in children with cancer. Accrual to the Phase I component at the adult recommended dose is ongoing and an expanded Phase II cohort in pediatric patients with ALL is planned. This study was sponsored by Talon Therapeutics and is supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Disclosures: No relevant conflicts of interest to declare.

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A Phase I Trial of Sirolimus (Rapamycin) in Pediatric Patients with Relapsed/Refractory Leukemia.

Blood ◽

10.1182/blood.v110.11.2834.2834 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2834-2834 ◽

Cited By ~ 2

Author(s):

Susan R. Rheingold ◽

Nancy Sacks ◽

Yueh J. Chang ◽

Valerie I. Brown ◽

David T. Teachey ◽

...

Keyword(s):

Phase I ◽

Dose Level ◽

Stable Disease ◽

Phase I Trial ◽

Pediatric Patients ◽

Loading Dose ◽

Mtor Inhibition ◽

Level 1 ◽

Dose Levels

Abstract Background: Downstream inhibition of the mammalian Target of Rapamycin (mTOR) pathway by sirolimus affects a variety of cellular functions including cap-dependent protein translation and cell cycle progression from the G1-to-S phase. Inhibition of mTOR also leads to dysregulation of the upstream signaling pathway that couples growth factor-receptor binding to mTOR activation through the PI-3 kinase/Akt pathway and may render PTEN-induced resistant lymphoblasts sensitive to agents that target the mTOR pathway. This hypothesis is supported by preclinical data which shows that sirolimus inhibits growth of ALL lines in vitro and has activity in a murine model of leukemia including ALL xenografts. Based upon these preclinical data we have piloted a Phase I trial of sirolimus in pediatric patients with relapsed acute leukemia. Methods: Pediatric patients with ≥ 2nd relapse of acute leukemia were enrolled in a Phase I dose escalation trial of oral daily sirolimus. We used a starting dose that is known to be well tolerated in pediatric renal transplant recipients and results in levels that inhibit ALL growth in vitro. At dose level 1, a loading dose of 9 mg/m2 was given on day 0, and 3 mg/m2 was given daily on days 1 to 21 or 28. Dose level 2 has a loading dose of 12 mg/m2 and daily dose of 4mg/m2. Sirolimus trough levels were obtained on days 3, 7, and end of cycle. Bone marrow aspirates (BM) were performed prior to therapy, and on day 7 (if no peripheral blasts) and day 21 or 28. Peripheral blood (PB) mononuclear cells and PB and/or BM lymphoblasts were obtained on days 0, 3, 7, 14, and 21/28 to evaluate the effect of sirolimus on intracellular targets, including ribosomal protein S6 (a pharmocodynamic marker of mTOR inhibition), 4e-BP1 and STAT5. Results: To date, 5 males and 3 females, ages 1–21, have been enrolled on study at the first 2 dose levels. Six patients had ALL, 1 infant had MLL(r) ALL, and 1 had AML. They had received 2–4 prior therapies. Three patients with ALL had stable disease at the end of the first cycle. One had a decrease in BM lymphoblasts from 39% to 12% by day 28 and a drop in absolute blast count (ABC) in the PB from 1134 to 290 but remained thrombocytopenic. The patient with MLL(r) infant ALL had a decrease in PB ABC from 62,415 to 0 by day 14 but had no change in BM lymphoblast % on day 21. Two of the 3 patients with stable disease progressed during their second cycle of therapy. The remaining 5 patients had progressive disease or were removed from study prior to the end of cycle 1 and were non-evaluable. At dose level 1 average trough level on day 7 was 10.9 (range 1–20.7) and at the end of the first cycle for non-progressors was 8.5 (range 5.8–12.2). There have been no DLTs attributable to sirolimus in any cycle to date. Preliminary immunoblots show hypophosphorylation of S6 in patients’ PB and BM after initiating sirolimus therapy. Conclusions: Sirolimus was well tolerated in pediatric patients due to its ease of administration and lack of toxicity. At the first and second dose levels there have been 2 patients and 1 patient with stable disease, respectively. Preliminary biologic data shows evidence of inhibition of mTOR, manifested by a decrease in phosphorylated S6, suggesting that S6 may be used as a biomarker for response to mTOR inhibition. Although sirolimus at these doses had a modest impact on the leukemia burden, it may be more effective when used in concert with other cytotoxic agents that inhibit cell growth and survival. Combined therapy is being investigated.

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Pharmacodynamic-guided, modified continuous reassessment method (mCRM)-based, dose finding study of rapamycin in adult patients with solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.3020 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 3020-3020 ◽

Cited By ~ 1

Author(s):

A. Jimeno ◽

P. Kulesza ◽

G. Cusatis ◽

A. Howard ◽

Y. Khan ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Level ◽

Dose Escalation ◽

Dose Finding ◽

Phase I Trials ◽

Dose Selection ◽

Normal Tissues ◽

Tumor Biopsies ◽

Dose Levels

3020 Background: Pharmacodynamic (PD) studies, using either surrogate or tumor tissues, are frequently incorporated in Phase I trials. However, it has been less common to base dose selection, the primary endpoint in Phase I trials, in PD effects. We conducted a PD-based dose selection study with rapamycin (Rap). Methods: We used the modified continuous reassessment method (mCRM), a computer-based dose escalation algorithm, and adapted the logit function from its classic toxicity-based input data to a PD-based input. We coupled this design to a Phase I trial of Rap with 2 parts: a dose estimation phase where PD endpoints are measured in normal tissues and a confirmation phase where tumor tissue is assessed. Patients (pts) had solid tumors refractory to standard therapy. Rap was given starting at 2 mg/day continuously in 3-pt cohorts. The PD endpoint was pP70S6K in skin and tumor. Biopsies were done on days 0 and 28 of cycle 1, and a PD effect was defined as ≥ 80% inhibition from baseline. The first 2 dose levels (2 and 3 mgs) were evaluated before implementing the mCRM. The data was then fed to the computer that based on the PD effect calculated the next dose level. The mCRM was set so escalation continued until a dose level elicited a PD effect and the mCRM assigned the same dose to 8 consecutive pts, at which point the effect of that dose will be confirmed in tumor biopsies. Other correlates were PET-CT and pharmacokinetics. Results: Ten pts were enrolled at doses of 2 mg (n = 4), 3 mg (n = 3) and 6 mg (n = 3). Toxicity was anemia (4 G1, 1 G2), leucopenia (1 G1, 2 G2), low ANC (2 G2), hyperglycemia (2 G1, 1 G2), hyperlipidemia (4 G1), and mucositis (1 G1, 1 G2). PD responses were seen in 2 and 1 pt at 2 and 3 mg dose levels. Input of data to the mCRM selected a dose of 6 mg for the third cohort, where PD effect was seen in 1 pt, and thus a fourth dose around 9 mg will be tested. No responses by RECIST occurred, but 2 pts had a response by PET. The PK was consistent with prior data (t1/2 24.6 ± 10.2 h, CL 31.4 ± 12.0 L/h, vol of distribution 235 ± 65 L), and exposure increased with dose. Steady-state concentration were in the 5–20 nM range. Conclusions: mCRM-based dose escalation based on real-time PD assessment is feasible and permits the exploitation of PD effects for dose selection in a rational manner. No significant financial relationships to disclose.

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Phase I study of topotecan and cisplatin in patients with advanced solid tumors: a cancer and leukemia group B study.

Journal of Clinical Oncology ◽

10.1200/jco.1994.12.12.2743 ◽

1994 ◽

Vol 12 (12) ◽

pp. 2743-2750 ◽

Cited By ~ 55

Author(s):

A A Miller ◽

J B Hargis ◽

R C Lilenbaum ◽

S Z Fields ◽

G L Rosner ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Level ◽

Phase Ii ◽

Dose Escalation ◽

Topoisomerase I ◽

Advanced Solid Tumors ◽

Phase Ii Trials ◽

Grade 3 ◽

Dose Levels

PURPOSE The objectives of this phase I trial were to determine the dose-limiting toxicities (DLTs) of the novel topoisomerase I inhibitor topotecan combined with cisplatin, to define the maximum-tolerated doses (MTDs) of the combination without and with the use of filgrastim, and to define recommended doses for phase II trials. PATIENTS AND METHODS Patients with advanced solid tumors were eligible if they had normal bone marrow, renal, and hepatic function and had not previously been treated with platinum compounds. Topotecan was administered intravenously on days 1 through 5 and cisplatin was administered intravenously on day 1 of a 21-day cycle. The topotecan dose was fixed at 1.0 mg/m2/d on the first four dose levels, and cisplatin was escalated in 25-mg/m2 increments from 25 to 100 mg/m2 without filgrastim. After encountering DLT, the dose of cisplatin was decreased by one level and topotecan dose escalation was attempted. After defining the MTD without growth factor, the study proceeded with escalating cisplatin doses to define the MTD with filgrastim 5 micrograms/kg subcutaneously (SC) daily starting on day 6 of treatment. Priming with filgrastim 5 micrograms/kg SC on days -6 to -2 before the first course was explored last. RESULTS Of 38 patients entered, 37 were eligible, 35 assessable for toxicity in the first course, and 28 assessable for response. The principal toxicity was grade 4 neutropenia, which had to last more than 7 days to be considered dose-limiting. No DLT was observed at the starting cisplatin dose of 25 mg/m2 (dose level 1). On level 2 (cisplatin 50 mg/m2, one patient had dose-limiting neutropenia and one patient had grade 3 renal toxicity. On level 3 (cisplatin 75 mg/m2), two patients had dose-limiting neutropenia. Therefore, cisplatin dose escalation was stopped. On dose level 5 (cisplatin 50 mg/m2 and topotecan 1.25 mg/m2/d), one patient had grade 4 neutropenia that lasted more than 7 days and one patient died of neutropenic sepsis. The remaining dose levels used topotecan 1.0 mg/m2/d plus cisplatin 75 mg/m2 (level 6) and 100 mg/m2 (levels 7 and 8) with filgrastim. No DLT was observed on level 6. On level 7, two patients had dose-limiting neutropenia and one patient had grade 3 hyperbilirubinemia. Priming with filgrastim on level 8 demonstrated no obvious advantage over level 7, and one patient had grade 4 thrombocytopenia that lasted more than 7 days. Three patients with non-small-cell lung cancer achieved a partial response and one patient with breast cancer had a complete response. CONCLUSION Topotecan and cisplatin in combination cause more neutropenia than expected from either drug given alone at the same dosage. The recommended phase II doses are topotecan 1.0 mg/m2/d for 5 days in combination with cisplatin 50 mg/m2 on day 1 without filgrastim or cisplatin 75 mg/m2 on day 1 with filgrastim support.

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Phase I dose-escalation study of the safety, tolerability, and pharmacokinetics of aflibercept in combination with S-1 in Japanese patients with advanced solid malignancies

Investigational New Drugs ◽

10.1007/s10637-019-00888-z ◽

2020 ◽

Vol 38 (5) ◽

pp. 1390-1399

Author(s):

Toshihiko Doi ◽

Narikazu Boku ◽

Yusuke Onozawa ◽

Keishiro Takahashi ◽

Osamu Kawaguchi ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Level ◽

Dose Escalation ◽

Japanese Patients ◽

Maximum Tolerated Dose ◽

Reversible Posterior Leukoencephalopathy Syndrome ◽

Pharmacokinetic Analysis ◽

Dose Escalation Study ◽

Posterior Leukoencephalopathy

SummaryBackground Aflibercept, a recombinant fusion protein binding VEGF-A, VEGF-B and placental growth factor, inhibits tumor growth by blocking angiogenesis. The aim of this phase I dose-escalation study was to determine the recommended phase II dose (RP2D) of aflibercept in combination with S-1 in Japanese patients with solid tumors. Patients and methods Sequential cohorts of 3–6 patients with metastatic or unresectable solid tumors, who had failed at least one prior line of standard treatment or who were not suitable for such treatment, were to receive escalating doses of aflibercept every 2 weeks, starting at 2 mg/kg, combined with S-1 at 40 mg/m2 twice daily (80 mg/m2/day; 4 weeks on/2 weeks off). Dose-escalation was to be based on the incidence of dose-limiting toxicity (DLT). Blood samples were collected for pharmacokinetic analysis. Results At the first dose level (aflibercept 2 mg/kg plus S-1) 1 of 6 patients experienced a DLT (grade 4 proteinuria). The aflibercept dose was consequently escalated to 4 mg/kg; 1 of 3 patients treated at this dose level had a DLT (grade 2 pleural effusion), and another patient experienced grade 3 reversible posterior leukoencephalopathy syndrome after the DLT assessment period. Additional patients were therefore enrolled into the first dose level to explore safety and tolerability. The study was subsequently terminated prematurely. The maximum tolerated dose was not reached and the RP2D was not determined in Japanese patients. Conclusions The tolerability and safety of aflibercept 2 mg/kg in combination with S-1 was confirmed in Japanese patients with advanced solid tumors.

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A phase I two arm trial of AS703569 (R763), an orally available aurora kinase inhibitor, in subjects with solid tumors: preliminary results

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.14130 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 14130-14130 ◽

Cited By ~ 11

Author(s):

J. S. Renshaw ◽

A. Patnaik ◽

M. Gordon ◽

M. Beeram ◽

D. Fischer ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Level ◽

Dose Escalation ◽

Kinase Inhibitor ◽

Aurora Kinase ◽

Aurora Kinases ◽

Dosing Regimens ◽

Level 1 ◽

Tumor Types

14130 Background: Aurora kinases are a family of kinases that play a crucial role in regulating segregation of chromosomes from parent to daughter cell and have been linked to tumorigenesis. Aurora kinase A is commonly amplified in solid tumors and has been established as an oncogene. Aurora B is often overexpressed and leads to defects in mitosis and increased tumor invasiveness. AS703569 is an orally available, highly potent inhibitor of aurora kinases A and B and several other kinases. AS703569 has been shown in vitro and in tumor xenograft models to inhibit proliferation and to trigger apoptosis of several tumor types. We report on the initial results of a phase I study of AS703569 in patients with solid tumors. The study objectives are to determine for each of 2 different dosing regimens the MTD and to evaluate safety, PK and pharmacodynamic effects. Methods: This is a phase I, two arm, dose-escalation study. Cohorts of 3 patients ≥18 years old with advanced solid tumors are being assigned to one of 2 dosing regimens. The dose escalation follows a modified Fibonacci scheme. The starting dose level is 6 mg/m2 p.o. per 21-day cycle divided in 2 or 3 doses (regimen 1: dosing on days 1, 8 or regimen 2: dosing on days 1, 2, 3). Patients with stable disease or response will be offered additional cycles. Results: A total of 15 patients have been included to date. The tumor types represent a typical widespread in phase I trials, including 3 cases of uterine/cervical cancer and 2 cases of breast cancer. The first 2 cohorts of 3 patients on dose level 1 (regimen 1 and 2) have been treated with no dose-limiting toxicities (DLTs) or serious adverse events (SAEs). Dose-escalation is proceeding for both regimens with 9 patients treated on dose level 2, 6 in regimen 1 where due to a DLT (likely disease-related and unlikely related to AS703569) the cohort was expanded, and 3 in regimen 2. Thus far, only two patients were withdrawn from the study due to disease progression and one patient withdrew consent. Two patients are ongoing at 4+ cycles and one at 3+. Conclusions: Treatment of patients in this phase I study of the aurora kinase inhibitor AS703569 at dose level 1 and 2 has been well tolerated over several cycles. Dose escalation is ongoing and analysis of PK and pharmacodynamics will be reported. No significant financial relationships to disclose.

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Phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with tofacitinib in patients with advanced pancreatobiliary cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3051 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3051-3051

Author(s):

Nebojsa Skorupan ◽

Mehwish Iqra Ahmad ◽

Guillaume Joe Pegna ◽

Cody J. Peer ◽

Jane B. Trepel ◽

...

Keyword(s):

Solid Tumors ◽

Dose Level ◽

Dose Escalation ◽

Single Agent ◽

Primary Objective ◽

Pseudomonas Exotoxin A ◽

Recombinant Immunotoxin ◽

Level 1 ◽

Expansion Cohort ◽

Almost All

3051 Background: LMB-100 recombinant immunotoxin consists of a mesothelin-binding Fab for targeting a modified Pseudomonas exotoxin A payload to tumors. Previous clinical trials demonstrated that almost all patients formed anti-drug-antibodies (ADAs) to LMB-100 that made administration beyond cycle 2 ineffective. Tofacitinib is an oral JAK inhibitor that prevented formation of ADAs against a closely related immunotoxin in pre-clinical studies. The primary objective of the dose escalation cohort was assessment of safety and tolerability of LMB-100 given with tofacitinib to patients with mesothelin-expressing solid tumors. The primary objective of the expansion cohort was to determine whether co-administration of tofacitinib delays formation of neutralizing LMB-100 ADAs. Methods: Patients (n = 13) with pancreatic adenocarcinoma and other mesothelin-expressing solid tumors (n = 3; cholangiocarcinoma, appendix, cystadenocarcinoma) were treated for up to 3 cycles with LMB-100 as a 30-minute infusion on days 4, 6, and 8 at two dose levels (100 and 140 mcg/kg) and co-treated with oral tofacitinib for the first 10 days of the cycle (10 mg BID). Results: Dose level 1 of LMB-100 was started at 100 mcg/kg one dose level below the single agent MTD. Dose escalation to 140 mcg/kg (dose level 2) resulted in DLTs in 2 of the 3 patients treated: grade 3 cardiac toxicity and grade 4 hyponatremia, both attributed to capillary leak syndrome. Ultimately, 7 patients were treated at dose level 1 without DLTs and 100 mcg/kg was chosen as the LMB-100 dose for the expansion cohort. The last of 6 patients treated in the expansion cohort developed grade 4 pericardial effusion leading to early closure of the study for toxicity. No objective responses were seen. Of the 8 patients who received two cycles of treatment at MTD, 4 met prespecified criteria for ADA prevention, and 2 patients who went on to receive cycle 3 had detectable LMB-100 plasma drug levels after administration. Conclusions: LMB-100 was unable to be co-administered safely with tofacitinib. ADA formation was prevented in 2 patients through 3 cycles, a rare occurrence. Clinical trial information: NCT04034238.

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A Safety Study of the Addition of Omacetaxine to the Standard-of-Care Induction Regimen of Cytarabine and Idarubicin in Newly-Diagnosed AML Patients

Blood ◽

10.1182/blood-2018-99-111412 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5218-5218

Author(s):

Sonia Christian ◽

Kelley E. Kozma ◽

Stephanie Barath ◽

Ardaman Shergill ◽

Damiano Rondelli ◽

...

Keyword(s):

High Risk ◽

Phase I ◽

Dose Level ◽

Dose Escalation ◽

De Novo ◽

Standard Of Care ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Induction Regimen ◽

Dose Levels

Abstract Background: Omacetaxine mepesuccinate (OM) is a semi-synthetic form of Homoharringtonine (HH), a cephalotaxine alkaloid. OM induces cell apoptosis by inhibiting peptide bond formation during mRNA translation, with rapid loss of short-lived proteins, such as MCL-1, c-MYC, and Cyclin D1 (Lu, J Hematol Oncol. 2014, 7: 2). Notably, cytarabine synergizes with HH in causing apoptosis of leukemia cells in vitro. A phase III RCT in China of 620 patients with de novo AML demonstrated superior CR and 3-yr survival rates upon addition of HH to a standard 2-drug AML induction therapy ('7 + 3'; Jin, Lancet Oncol. 2013, 14:599). Thus, we hypothesized that OM, at an appropriate dose, would similarly enhance the efficacy of a 7 + 3 regimen. OM is FDA-approved for the treatment of TKI-resistant CML. The MTD of 1.25 mg/m2/d SQ for 14 days every 28 days, as determined in a phase I/II CML trial of OM (Quintás-Cardama, Cancer 2007, 109: 248), served as a basis for the dose escalation used in this study. Methods: The primary endpoint of this phase I safety trial was to determine the optimally safe and active dose (OD) of OM when added to a standard 7 + 3 induction regimen, cytarabine and idarubicin. OM was administered SQ q12h d1-7 with cytarabine (100mg/m2 CIV) d1-7 and idarubicin (12mg/m2 IV) d1-3. Four dose levels were tested, starting with OM 0.625 mg/m2 q12h (further dose levels: 1.25, 2.0, 3.0, and 4.2 mg/m2 q12h). All newly diagnosed, untreated de novo or secondary AML patients, aged 18-70y with ECOG PS of 0-3 were eligible for this study. Secondary endpoints included overall response rate (ORR) and overall and event free survival (OS, EFS). Hematologic toxicity (HT) was defined as incomplete hematologic recovery; ANC < 1.0 x 109/L or platelet count < 100 x 109/L present at d49, with the bone marrow documented to be free of leukemic infiltration. Dose escalation was based on the EffTox design (Biometrics 2004, 60:684), a Bayesian adaptive design which considers the trade-off between efficacy and toxicity in determining the OD for Phase II trials. Results: Twenty-two patients, median age 58 (range 25-69) years were enrolled from June 2015 to June 2018. 12 patients (54.5%) had adverse cytogenetics, 6 (27%) intermediate risk, 3 (13.7%) favorable risk and 1 patient's cytogenetic risk was unknown (fibrotic BM). Eight patients demonstrated disease evolution from myelodysplastic syndrome (MDS). Altogether 16 of the 22 patients (73%) were deemed high risk based on cytogenetics or MDS-AML evolution. The EffTox design was implemented until cohort 4 (3 mg/m2 q12h), where 2 of 3 patients experienced a grade 5 non-hematologic toxicity (NHT), resulting in a dose-limiting toxicity (DLT). Since no DLTs were observed in cohort 3, an additional 5 patients were thus enrolled at this dose level to ensure safety. The OD was determined to be the dose level used in cohort 3: OM 2 mg/m2. No HTs were observed in 21 of 22 patients, (one patient not evaluable). The most common non-hematologic treatment emergent adverse events (TEAEs) of any grade were fever (68%), nausea (64%), vomiting (55%), hyperglycemia (41%), diarrhea (41%), mucositis (36%), headache (36%), sinus tachycardia (32%), rash/dermatitis (32%), and abdominal pain (32%). The most prevalent non-hematologic grade 3/4 TEAEs were febrile neutropenia (23%), hypoxia (18%), hyperglycemia (18%), and dyspnea (18%). ORR (CR and CRi) was 45.5%. Median OS was 605 days and EFS was 100 days. Conclusion: In this population with predominantly high-risk AML, the combination of OM with a standard 7 + 3 regimen demonstrates a manageable safety profile with acceptable efficacy. As ~ 25% of patients achieving CR with '7 + 3' do so after a second induction (based on meta-analysis of 6 trials, n = 1980, see Cancer 2010, 116: 5012), the ORR here is comparable to those receiving a single standard of care induction. The results in this high-risk group are therefore promising and warrant further investigation in a phase II trial. At present, we are assessing leukemic blast MCL protein expression in stored pre-treatment samples to determine if this predicts OM efficacy. NCT02440568. Teva has performed a Medical Accuracy Review of this abstract. Figure. Figure. Disclosures Khan: Teva: Speakers Bureau. Patel:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.

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Low-dose metronomic topotecan and pazopanib in children with recurrent or refractory solid tumors: A C17 Canadian phase I trial (TOPAZ).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.10020 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 10020-10020

Author(s):

Arif Manji ◽

Daniel A. Morgenstern ◽

Yvan Samson ◽

Rebecca Deyell ◽

Donna Johnston ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Stable Disease ◽

Low Dose ◽

Pediatric Patients ◽

Novel Approach ◽

Best Response ◽

Grade 3 ◽

Relapsed Disease

10020 Background: Low-dose metronomic topotecan (mTP) represents a novel approach to chemotherapy delivery which, in preclinical models, may work synergistically with pazopanib (PZ) in targeting angiogenesis. This study was designed to determine the recommended phase 2 dose (RP2D) of mTP/PZ in pediatric patients with solid tumors, while describing the safety and toxicity of this regimen. Methods: A phase I dose-escalation, pharmacokinetic (PK) and pharmacodynamic (PD) study of mTP/PZ was conducted at ten sites across Canada, enrolling pediatric patients aged 2-21 years with relapsed/refractory solid tumors. Patients were treated with oral mTP and PZ suspension daily without interruption in 28-day cycles, with dose escalation in accordance with the rolling-six design. Five dose levels (0.12/125, 0.16/125, 0.22/125, 0.22/160, and 0.3/160 mg/m2/day of mTP/PZ) were evaluated. PK studies were performed on day 1 and at steady state, and PD studies included circulating angiogenic factors VEGFR1, VEGFR2, VEGF, endoglin and placental growth factor. Results: Thirty patients (pts) were enrolled, of whom 26 were evaluable for dose-limiting toxicity (DLT), with median age 12 years (3-20). The most common diagnoses included osteosarcoma (8), neuroblastoma (NB, 7), Ewing sarcoma/PNET (4), and rhabdomyosarcoma (4). The most common grade 3/4 adverse events (AEs) related to protocol therapy were neutropenia (18%), thrombocytopenia (11%), lymphocytopenia (11%), AST elevation (11%), and lipase elevation (11%). Only 2 cycle-1 DLTs were observed on study, both at the 0.3/160 mg/m2 mTP/PZ dose level (2/5 pts) comprising persistent grade 3 thrombocytopenia and grade 3 ALT elevation. No AEs experienced beyond cycle-1 required treatment discontinuation. Best response was stable disease in 10/25 pts (40%) for a median duration of 6.4 months (1.7-45.1). One patient with refractory NB achieved stable disease for 45 months and continued on mTP/PZ via compassionate access after study closure. PK and PD results are pending at this time. Conclusions: The combination of oral mTP and PZ is safe and tolerable in pediatric patients with solid tumors, with a RP2D of mTP 0.22 mg/m2/day and PZ suspension 160 mg/m2/day. Ten patients achieved stable disease for a median of 6 months. The lack of objective responses suggests that this combination is likely of limited benefit for relapsed disease, but may play a role as maintenance therapy. Clinical trial information: NCT02303028.

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Addition of Oxaliplatin to Continuous Fluorouracil, l-Folinic Acid, and Concomitant Radiotherapy in Rectal Cancer: The Lyon R 97-03 Phase I Trial

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.9.2433 ◽

2001 ◽

Vol 19 (9) ◽

pp. 2433-2438 ◽

Cited By ~ 82

Author(s):

Gilles Freyer ◽

Nadine Bossard ◽

Pascale Romestaing ◽

Françoise Mornex ◽

Olivier Chapet ◽

...

Keyword(s):

Rectal Cancer ◽

Phase I ◽

Folinic Acid ◽

Dose Level ◽

Dose Escalation ◽

Local Treatment ◽

Rectal Adenocarcinoma ◽

Severe Diarrhea ◽

Phase Ii Studies ◽

Level 1

PURPOSE: Oxaliplatin could increase the efficacy of fluorouracil (5-FU)/folinic acid chemoradiotherapy in rectal cancer. We tested three dose levels to identify a feasible oxaliplatin dose for combination therapy. PATIENTS AND METHODS: Between February 1998 and April 2000, we included 17 rectal adenocarcinoma patients in a single-center phase I study. Patients had T4 rectal carcinoma, T1-T3 disease with colostomy refusal, or potentially operable T2/T3 M1 requiring local treatment. Pelvic radiotherapy was 45 Gy over 5 weeks, 1.8 Gy/fraction, with concomitant chemotherapy weeks 1 and 5. Chemotherapy was oxaliplatin 80, 100, or 130 mg/m2 2-hour infusion on day 1 followed by l-folinic acid 100 mg/m2/d intravenous bolus, and 5-FU 350 mg/m2/d continuous infusion on days 1 to 5 (FolfoR1). Six patients refusing surgery received additional contact radiotherapy +/− brachytherapy. Dose escalation proceeded if less than two of six patients had dose-limiting toxicity (DLT) at a given dose-level. RESULTS: All except two patients completed treatment; patients at level 1 (prolonged grade 1 thrombocytopenia) and level 3 (prolonged cold-related dysesthesia) had no second chemotherapy course. Median follow-up is 14 months (range, 2 to 28 months). One elderly patient at dose level 1 had DLT asthenia, severe diarrhea and vomiting, and more than 10% weight loss. There were no other DLTs and no severe rectitis or gastrointestinal toxicity. There were objective responses at all doses and no progressions. Eight patients underwent radical surgery after chemoradiotherapy. Two had complete pathologic responses. CONCLUSION: FolfoR1 seems feasible and effective. Dose escalation did not increase toxicity. Although the MTD was not reached in this study, we recommend oxaliplatin 130 mg/m2 for phase II studies because it is the dose determined from studies in metastatic patients with no toxicity when given concurrently with radiation.

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