|Year : 2014 | Volume
| Issue : 1 | Page : 40-44
Phase 1 dose escalation study of rigosertib by 2-, 4-, or 8-hour infusion twice-weekly in patients with advanced cancer
SH Advani1, SD Achrekar1, DC Doval2, D Raghunadharao3, FE Wilhelm4, M Acharya4
1 Department of Medical Oncology, Jaslok Hospital and Research Centre, 15 Dr. Deshmukh Marg, Pedder Road, Mumbai, Maharashtra, India
2 Rajiv Gandhi Cancer Institute and Research Centre, Sector 5, Rohini, New Delhi, India
3 Department of Medical Oncology, Nizam's Institute of Medical Sciences, Panjagutta, Hyderabad, India
4 Department of Onconova Therapeutics, Inc, 375 Pheasant Run Newtown, PA 18940, USA
|Date of Web Publication||18-Jun-2014|
Department of Medical Oncology, Nizam's Institute of Medical Sciences, Panjagutta, Hyderabad
Source of Support: The funding for this clinical study was provided by Onconova Therapeutics, Inc., Conflict of Interest: None
Context: Rigosertib, a potent, multi-kinase inhibitor that selectively induces mitotic arrest and apoptosis in cancer cells and is non-toxic to normal cells, is being developed for the treatment of solid tumors and hematological malignancies. Aims: To determine the safety, dose-limiting toxicities, and clinical activity of rigosertib administered by 2-, 4-, or 8-hour continuous IV infusion twice-a-week for 3 weeks out of a 4-week cycle in patients with advanced solid tumor or hematological malignancies; and to confirm the safety and tolerability of the recommended phase 2 dose (RPTD). Settings and Design: Phase 1, open-label, dose-escalation study in men and women ≥18 years of age. Materials and Methods: An escalation phase optimized the duration of infusion (2, 4, or 8 hours) of 3200 mg rigosertib twice-a-week for 3 weeks of a 4-week cycle; an expansion phase confirmed the maximum tolerated dose (MTD). Statistical Analysis Used: All data summaries were descriptive. PK parameters were estimated using compartmental analysis. Results: 25 patients (16 male, 9 female, 26-66 years, all Asian) were treated with rigosertib, 16 in the escalation phase; 9 in the expansion phase. MTD was determined to be 3200 mg as a 4-hour infusion and 2400 mg over 4 hours was declared to be the RPTD. Best response was stable disease in 5 of 14 evaluable patients, with a mean (range) of 90 (43-108) days. Conclusions: 2400 mg rigosertib as a 4-hour infusion was identified as the RPTD. Five patients achieved stable disease lasting 6-16 weeks.
Keywords: Rigosertib, pharmacokinetics, ovarian, pancreatic, response evaluation criteria in solid tumor, eastern cooperative oncology group, dose-escalation
|How to cite this article:|
Advani S H, Achrekar S D, Doval D C, Raghunadharao D, Wilhelm F E, Acharya M. Phase 1 dose escalation study of rigosertib by 2-, 4-, or 8-hour infusion twice-weekly in patients with advanced cancer. Indian J Cancer 2014;51:40-4
|How to cite this URL:|
Advani S H, Achrekar S D, Doval D C, Raghunadharao D, Wilhelm F E, Acharya M. Phase 1 dose escalation study of rigosertib by 2-, 4-, or 8-hour infusion twice-weekly in patients with advanced cancer. Indian J Cancer [serial online] 2014 [cited 2021 Jul 25];51:40-4. Available from: https://www.indianjcancer.com/text.asp?2014/51/1/40/134617
| » Introduction|| |
Rigosertib is a potent and selective multi-kinase inhibitor that selectively induces mitotic arrest and apoptosis in cancer cells, while being non-toxic to normal cells. , This study explored 4- and 8-hour continuous infusions of rigosertib as an alternative to the 2-hour twice-a-week infusion schedule that had been used in a prior phase 1 trial conducted at John Hopkins Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.  It also evaluated the benefit of extending exposure to rigosertib as the drug has a very short half-life.
| » Materials and Methods|| |
The study was organized in two phases: A two-stage escalation phase (to evaluate the safety of various ascending doses and schedules) and a confirmation phase to determine the maximum tolerated dose [Table 1]. During stage 1 of the escalation phase, the duration of infusion was assessed in 3 consecutive cohorts consisting of either 2-hour, or 4-hour, or 8-hour infusion twice-a-week for the first 3 weeks of each 4-week cycle, until evidence of disease progression or intolerable adverse events were seen. The starting dose was 3200 mg per patient, which was established in a prior study. 
Once the last patient of each cohort completed cycle 1 safely, the duration of the infusion was increased from 2 hours to 4 hours and then to 8 hours. The longest tolerable duration of dosing was advanced to stage 2 and used in all subsequent cohorts. Safety monitoring was done for at least 4 weeks in the last patient of each cohort before escalation to the next dose cohort. During stage 2 of the escalation phase (dose optimization), tolerability associated with dose was assessed in one cohort of 4000 mg. The maximum tolerated dose (MTD) was declared at the longest infusion schedule and highest dose that did not result in dose-limiting toxicity. After data were evaluated in the 16 patients in the dose escalation phase, a 4-hour infusion of the MTD (and prospective recommended phase 2 dose - RPTD) was administered twice-a-week for the first 3 weeks of a 4-week cycle to confirm the safety and tolerability of the RPTD.
For patients with measurable disease, efficacy was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0). Hematological responses were evaluated according to 2006 International Working Group criteria, Acute Myeloid Leukemia 2003 criteria and Chronic Lymphocytic Leukemia 1996 criteria. For patients with hematological malignancies, bone marrow aspirates and karyotypes were performed at baseline and at least every other cycle until disease progression. Safety variables included physical examination, weight, Eastern Cooperative Oncology Group (ECOG) performance status (at week 1 of each 4-week cycle), clinical laboratory tests, and other clinical safety findings.
All data summaries were descriptive. Pharmacokinetic parameters were evaluated at cycle 1 week 1 and cycle 3 week 1 and were estimated using compartmental analysis.
| » Results|| |
Demographics and baseline characteristics
Of the 37 screened patients, 25 (16 male, 9 female, age 25.7-65.8 years, all of Asian ethnic origin) were enrolled and treated with rigosertib. ECOG status was 0 in 16 of the patients, 1 in 2 patients, and 2 in 7 patients. The primary sites of cancer were ovary (6 patients) and pancreas (4 patients), followed by bone marrow, gall bladder, stomach, and tongue (2 patients each), and femur (osteosarcoma), periampullary, liver, oesophagus, rectum, kidney (renal cell), and thymus gland (1 patient each). Adenocarcinoma was the most common histopathology (present in 13 patients). Distant metastases were present in 23 patients, liver metastasis in 14, lymph nodes in 13, lung in 11, bone in 3 and other sites in 6. The average duration of disease was 30.5 months (range: 0.2-80.8) in the 22 patients for whom duration was known.
Of the 25 treated patients, 24 (96%) had received prior therapy, including chemotherapy (23 patients), radiation therapy (6 patients), and immunotherapy (1 patient). Nine patients had undergone prior surgery. Twenty-four patients (96%) were taking at least one concomitant medication, the most common of which were analgesics (66.7%), drugs for dyspepsia (66.7%), anti-bacterials (62.5%), drugs for functional gastrointestinal disorders (54.2%), and blood substitutes and perfusion solutions (45.8%). Compliance with treatment was 100% for all patients.
Sixteen patients were treated in the escalation phase, with a starting dose of 3200 mg administered as a 2-hour infusion. The overall response in the intent-to-treat population is summarized by dose group and by duration of infusion in [Table 2]. Of the 14 patients evaluable for response, none had a complete or partial response to therapy. The best response seen was stable disease in 5 patients (35.7%) with a maximum duration of approximately 16 weeks (range of 43-108 days). Four of these patients were treated at 3200 mg and 1 at 2400 mg. The primary diagnoses of these 5 patients with stable disease were thymoma, hepatocellular carcinoma, carcinoma of pancreas, carcinoma of the gallbladder, and chronic myelocytic leukemia (CML). All 5 patients had received prior chemotherapy. Nine patients (9/14, 64.3%) had progressive disease at the end of cycle 2, with a median time to tumor progression of 49.5 days (95% CI 43.2-72 days). The overall response at the last evaluation was progressive disease for all 14 evaluable patients.
|Table 2: Summary of overall response for the cycle, by dose group and duration of infusion-intent-to-tyreat population|
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The 4-hour infusion was declared to be the longest tolerable duration in stage 1 of the escalation phase and was used in all subsequent cohorts of the dose optimization stage (stage 2). During stage 2 of the escalation phase, a dose-limiting toxicity (DLT) was identified in 2 of the first 4 patients enrolled in the rigosertib 4000 mg cohort: Grade 3 hyponatremia in 1 patient and severe abdominal pain in the other. Therefore, the 3200 mg dose administered over 4 hours was declared to be the maximum tolerated dose (MTD) and schedule.
During the confirmation phase, a 4-hour infusion of a 3200 mg dose was to be administered twice-a-week for the first 3 weeks of a 4-week cycle to 9 patients. Among the first 4 patients, 1 patient (diagnosed with pancreatic cancer with multiple liver metastasis) died after developing hepatic encephalopathy (considered a > grade 3 DLT) after the first dose of 3200 mg rigosertib. In light of this serious AE, and per protocol, the dose was reduced by 25% (from 3200 mg to 2400 mg) for all ongoing and future patients. No DLT ≥ grade 3 was seen at the 2400 mg dose in the 4-hour infusion; thus, 2400 mg was declared to be the RPTD.
Blood samples were collected pre-treatment (just prior to infusion); at 1, 2, 4, and 8 hours during the infusion; and at 10, 20, 30 minutes and 1, 2, 4, 8, 24, and 48 hours after the infusion. The drug, ON 01910.Na. Concentrate was assayed by validated bioanalytic method (HPLC or LC/MS/ MS). Calibrations were carried out using human plasma samples spiked with known quantities of the analyte. The following parameters for ON 01910 were calculated by non-compartmental analysis: Cmax, Css, Tmax, AUClast, AUCinf, %AUC extrapolated, Clearance, terminal half-life, MRT, and volume of distribution at steady-state.
The plasma profile of the drug as a function of the duration of infusion is shown in [Figure 1]. Plasma pharmacokinetic parameters are summarized in [Table 3]. The Cmax of the drug increased with the decrease in the duration of the infusion. Also, the maximum concentrations were achieved during the infusion phase of the drug. The drug appears to clear rapidly from plasma with a functional half-life of less than 3 hours. The pharmacokinetic parameters for the 2-hour infusion schedule seems to be consistent with the observed parameters in the initial phase I study conducted at Johns Hopkins University. 
|Table 3: Mean (CV%) pharmacokinetic parameters after 2-, 4-, or 8-hour continuous intravenous infusion of ascending doses of rigosertib in patients with advanced cancer, by dose group|
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Out of 25 patients in the study, 24 patients experienced at least one treatment-emergent adverse event (TEAE). TEAEs are summarized by dose group and by duration of infusion in [Table 4]; TEAEs reported in at least 10% of patients are listed by dose group in [Table 4] and by duration of infusion in [Table 5]. TEAEs of at least grade 3 were reported for 11 patients: 4 (36.4%) in the 2400 mg dose group, 5 (45.5%) in the 3200 mg dose group, 2 (18.2%) in the 4000 mg dose group. Drug-related TEAEs of at least grade 3 were reported for 4 patients: Three in the 3200 mg group (2 patients with anemia and 1 with hepatic encephalopathy) and 1 in the 4000 mg group (hyponatremia and asphyxia). Dose-limiting toxicities (DLTs) were reported for 4 patients (2 each in the 3200 mg group and the 4000 group), as shown in [Table 6].
|Table 4: Summary of treatment-emergent adverse events, by dose group and duration of infusion– intent-totreat|
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|Table 5: Number and percent of patients with most frequently reported (≥ 10% of patients) treatmentemergent adverse events, by system organ class and preferred term within dose group and duration of infusion – intent-to-treat population|
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Serious adverse events were reported for 10 patients, including 4 deaths. Of these 10 patients, 4 had SAEs that were considered to be possibly related to study drug (asphyxia and hyponatremia, anemia, hiccough and dizziness, and hepatic encephalopathy). Two of these 4 possibly-related SAEs led to death. One patient was a 44-year-old male with poorly differentiated gastric carcinoma who experienced nausea, backache, and abdominal distension due to ascites after receiving one dose of rigosertib. Two days later, he developed altered sensorium and abnormal gait and was found to have grade 3 hyponatremia that was considered possibly related to study drug. Death due to asphyxia/gastric content aspiration occurred 2 days later (4 days after the dose of rigosertib).
The other patient was a 66-year-old male with pancreatic carcinoma who developed altered mental status, irritability, and incoherent speech one day after receiving the first dose of rigosertib. He was diagnosed with and hospitalized due to hepatic encephalopathy. Death due to hepatorenal failure, considered possibly related to/aggravated by rigosertib, occurred the following day.
| » Discussion|| |
A novel small molecule, rigosertib, selectively induces mitotic arrest and apoptosis in cancer cells, while being non-toxic to normal cells. , Rigosertib has been shown to affect both, the growth (mediated by the phosphoinositide 3 [PI-3], mTOR and Akt signaling pathways) and the apoptotic pathways (mediated by the Jun kinase), resulting in mitotic block and cell death in cancer cells.  Rigosertib uniquely inhibits both, the PI-3 kinase and polo-like kinase (PLK)1 pathways, inducing polynumeric centrosomes and ultimately dysregulation of mitosis.  This multi-pathway inhibitory nature of rigosertib is noteworthy; not only has PLK1 been postulated as one of the last cell cycle arrest points,  but the PI-3 K inhibitory activity also adds to the anti-cancer potential of rigosertib. It also induces several pro-apoptotic factors of the Bcl family and inhibits the accumulation of anti-apoptotic proteins including Mcl-1.  At the molecular level, rigosertib inhibits the PI-3 kinase (particularly α and α subtypes), the extracellular signal-regulated kinase (ERK; growth), and the Akt (pro-survival) pathways.  This open-label, dose-escalating phase 1 study of rigosertib in patients with advanced cancers included a 2-stage (duration optimization and dose optimization) escalation phase followed by a confirmation phase. The starting dose of 3200 mg rigosertib administered intravenously over 2 hours twice-a-week for the first 3 weeks of a 4-week cycle was selected based on results of a prior phase 1 trial conducted at John Hopkins Kimmel Comprehensive Cancer Center, Baltimore, MD, USA, with dose escalation up to 4370 mg administered twice-a-week, for the first 3 weeks of a 4-week cycle.  Of the 25 patients who were treated with rigosertib, 16 were treated during the escalation phase. The longest tolerable duration in stage 1 of the escalation phase was 4 hours, which was the duration used in all subsequent cohorts of the dose optimization stage. Due to dose-limiting toxicity at the 4000 mg dose, the dose of 3200 mg was determined to be the maximum tolerated dose (MTD) and was the starting dose in the confirmation phase. After a DLT occurred among the 9 patients in the confirmation phase, the dose was reduced by 25% (from 3200 mg to 2400 mg), and the 2400 mg dose was determined to be the RPTD.
Eleven of the 25 patients with solid tumors discontinued before completing cycle 2 and were excluded from the efficacy analysis. Of the 14 patients evaluable for response, none had a complete or partial response to treatment. The best response seen during the study was stable disease in 5 (35.7%) of the 14 evaluable patients that lasted for 16 weeks in 4 patients and for 8 weeks in 1 patient.
The plasma concentrations reached a maximum at the end of the infusion and then declined rapidly. The systemic clearance of rigosertib at the recommended dose of 2400 mg (n = 5) is 2.6 L/h/m 2 and the half-life is 4.6 hours.
| » Conclusions|| |
This phase 1 study identified 2400 mg rigosertib administered as a 4-hour infusion to be the RPTD. Overall, the drug was well tolerated, and stable disease was observed in 5 of 14 evaluable patients.
| » Acknowledgment|| |
The authors wish to thank Drs James Holland and Sridhar Mani, who provided excellent advice in the design of this study, Dr Khan, who provided regulatory assistance, and Max Neeman International (CRO) who successfully conducted the study on behalf of the Sponsor. Ms Barbara Snyder is also recognized for excellent editorial assistance.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]
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