Date: 2015-05-31
Type of information: Presentation of results at a congress
phase: 1-2
Announcement: presentation of results at the American Society of Clinical Oncology (ASCO) annual meeting, in Chicago
Company: Threshold Pharmaceuticals (USA - CA)
Product: evofosfamide (TH-302)
Action
mechanism: TH-302 is a hypoxia-activated prodrug consisting of a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard. The product has been discovered by Threshold scientists. It is designed as a prodrug that is selectively activated under the extreme hypoxic conditions commonly found in tumors, but not typically in healthy tissues. Within regions of tumor hypoxia, TH-302 is converted to its active form, bromo isophoramide mustard (Br-IPM). Variants of IPM are clinically validated potent DNA alkylating agents, which kill tumor cells by causing DNA to crosslink thereby rendering cells unable to replicate their DNA and divide. Once activated in hypoxic tissues, Br-IPM can also diffuse into surrounding oxygenated regions of the tumor and kill cells there via a “bystander effect”. Evofosfamide is currently in Phase 3 clinical trials in locally advanced or metastatic pancreatic cancer and advanced soft tissue sarcoma.
In February 2012, Merck KGaA signed a global agreement to co-develop and commercialize TH-302 with Threshold. Under the terms of the agreement, Merck KGaA received co-development rights, exclusive global commercialization rights with Threshold retaining an option to co-commercialize the therapeutic in the United States.
Disease: multiple myeloma
Therapeutic area: Cancer - Oncology
Country:
Trial details:
Latest
news: * On May 31, 2015, Threshold Pharmaceuticals announced new preliminary data from the Phase 2 component of an ongoing Phase 1/2 trial of evofosfamide (TH-302) in combination with the proteasome inhibitor Velcade® (bortezomib) and low-dose dexamethasone ("EBorD") in patients with relapsed/refractory multiple myeloma. A clinical benefit rate of 29% (one complete response, two partial responses, and one minimal response) was observed in patients treated at the recommended Phase 2 dose of evofosfamide (340 mg/m2) in EBorD. Objective responses were observed in heavily pretreated patients (median of 8 prior systemic therapy regimens) including prior treatment with bortezomib (median of 3 prior bortezomib-containing regimens). The data are being presented at American Society of Clinical Oncology (ASCO) meeting in Chicago, Illinois (Abstract #8579). The ongoing Phase 1/2 trial is investigating evofosfamide and dexamethasone with or without bortezomib with respect to safety and tolerability, dose-limiting toxicities and the maximum-tolerated dose of evofosfamide, and preliminary efficacy in patients with relapsed/refractory multiple myeloma. The recommended Phase 2 dose of evofosfamide in EBorD was previously established at 340 mg/m2. A total of 25 patients with relapsed/refractory multiple myeloma have been enrolled in the EBorD component of the study as of May 1, 2015 . At the ASCO meeting, preliminary safety and efficacy analyses were presented from 18 patients who initiated therapy prior to December 1, 2014 , with presented analyses reflecting data in the clinical database as of May 2015 . Key preliminary data from EBorD dosing cohorts presented at ASCO include: * On November 6, 2014, Threshold Pharmaceuticals announced that new data from an ongoing Phase 1/2 trial evaluating TH-302 and low-dose dexamethasone with or without the proteasome inhibitor bortezomib (Velcade®) in patients with relapsed/refractory multiple myeloma will be presented in a poster at the 56th Annual Meeting of the American Society of Hematology (ASH) held in San Francisco, California , from December 6 - 9, 2014 (Abstract #2142). The poster titled, "Phase 1/2 Trial of TH-302 and Dexamethasone without or with Bortezomib (TBorD) in Patients with Relapsed/Refractory Multiple Myeloma" (Abstract #2142) will be presented during Session 653 titled, "Myeloma: Therapy, excluding Transplantation: Poster I" on Saturday, December 6, 2014 from 5:30 PM - 7:30 PM at the Moscone Center, West Building , Level 1. * On May 30, 2014, Threshold Pharmaceuticals announced new preliminary clinical data from an ongoing company-sponsored Phase 1/2 trial of its investigational hypoxia-activated prodrug, TH-302, in combination with low-dose dexamethasone in patients with relapsed/refractory multiple myeloma. The results are being presented as part of the poster highlights session on Lymphoma and Plasma Cell Disorders at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago [Abstract #8534 (Poster #14)]. The objectives of the ongoing Phase 1/2 trial include determining the safety and tolerability of TH-302 and dexamethasone, the dose-limiting toxicities and the maximum-tolerated dose of TH-302, and assessing preliminary signals of clinical activity in patients with relapsed/refractory multiple myeloma. The dose of TH-302 administered in the dose escalation portion of the study was 240, 340, or 480 mg/m2 (depending on the dose cohort into which a patient enrolled) given on days 1, 4, 8, and 11 of a 21-day cycle, with 40 mg dexamethasone given on the same days as TH-302. Previously, the maximum tolerated dose was reported to be 340 mg/m2 TH-302. Enrollment of patients with relapsed/refractory multiple myeloma in the dose-escalation and dose-expansion portions of the study is now complete, including 24 patients enrolled at the maximum tolerated dose of TH-302 (340 mg/m2). Patients had received a median of 6.5 systemic therapies prior to enrollment. The ASCO presentation includes data from 24 patients in the dose-escalation and dose-expansion portions of the study who initiated treatment prior to March 1, 2014 ; analyses reflect the clinical database as of May 19, 2014 . Of these 24 patients, 17 were treated at the maximum tolerated dose of TH-302. Preliminary assessment of safety and tolerability: The most common adverse events related to TH-302 occurring in at least 25% of patients were nausea and fatigue. The most common Grade 3/4 hematologic adverse events related to TH-302 were thrombocytopenia (29%) and leukopenia (25%). Dose-limiting toxicities of Grade 3 stomatitis were reported during the first treatment cycle for the first two patients treated at 480 mg/m2 TH-302; therefore, the maximum tolerated dose of TH-302 was established at 340 mg/m2.
Preliminary assessment of safety and tolerability: Preliminary safety and tolerability results from the 18 patients included in the ASCO presentation support further investigation of evofosfamide in patients with relapsed/refractory multiple myeloma. The most common Grade 3/4 hematological adverse events were thrombocytopenia (reported in 11 patients), anemia (reported in 6 patients), and neutropenia (reported in 4 patients). Nausea (reported in 8 patients; one Grade 3/4) and fatigue (reported in 7 patients; one Grade 3/4) were the most common non-hematological adverse events. Eleven serious adverse events (SAEs) were reported in 9 patients. The only SAE occurring in more than one patient were two events of colitis. Neither event was considered related to evofosfamide. Five SAEs were considered as related to evofosfamide: bronchiolitis, melena, pneumonia, thrombocytopenia and viral infection. Skin toxicity and mucosal toxicities were not dose limiting. Rash was reported in five patients; stomatitis, skin lesion, pruritus and skin hyperpigmentation were each reported in one patient; none of these were Grade 3 or higher. No patients discontinued treatment due to an adverse event. There were no deaths related to study drug.
Preliminary assessment of clinical activity: Preliminary results from the 18 patients included in the ASCO presentation suggested anti-myeloma activity of EBorD therapy. According to modified International Myeloma Working Group (IMWG) criteria,2,3 responses included one complete response (CR), two partial responses (PRs), one minimal response (MR) and eleven stable disease (SD) assessments; three patients had progressive disease (PD). The patients with the CR and PRs had all previously undergone autologous transplantations and had received prior current standard treatment including IMiDs (a class of immunomodulators), proteasome inhibitors (including bortezomib), dexamethasone, and at least one conventional alkylating agent.
Preliminary assessment of clinical activity: Of the 24 patients included in the ASCO presentation, 23 were evaluable for response. According to modified International Myeloma Working Group (IMWG) criteria, best responses included four partial responses (4 PR), two minimal responses (2 MR), and 15 stable disease (15 SD) assessments; two patients had progressive disease (2 PD). The clinical benefit rate for patients treated at the maximum tolerated dose of TH-302 (n=16 evaluable patients) was 31% (comprised of 3 PR and 2 MR)
