Stew Kroll

Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of TH-302, a Hypoxia-Activated Prodrug, in Patients with Advanced Solid Malignancies

Purpose: The objectives of this phase 1, first-in-human study were to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), safety, pharmacokinetics, and preliminary activity of the hypoxia-activated prodrug TH-302 in patients with advanced solid tumors. Experimental Design: TH-302 was administered intravenously over 30 to 60 minutes in two regimens: three times weekly dosing followed by 1 week off (arm A) and every 3-week dosing (arm B). Results: Fifty-seven patients enrolled (arm A: N = 37 and arm B: N = 20). The TH-302 dose was escalated from 7.5 to 670 mg/m2 in arm A and from 670 to 940 mg/m2 in arm B. The most common adverse events were nausea, skin rash, fatigue, and vomiting. Hematologic toxicity was mild and limited. Grade 3 skin and mucosal toxicities were dose limiting at 670 mg/m2 in arm A; the MTD was 575 mg/m2. In arm B, grade 3 fatigue and grade 3 vaginitis/proctitis were dose limiting at 940 mg/m2; the MTD was 670 mg/m2. Plasma concentrations of TH-302 and the active metabolite Br-IPM (brominated version of isophosphoramide mustard) increased proportionally with dose. Two partial responses were noted in patients with metastatic small cell lung cancer (SCLC) and melanoma in arm A at 480 and 670 mg/m2. Stable disease was observed in arms A and B in 18 and 9 patients, respectively. Conclusions: The MTD of TH-302 was 575 mg/m2 weekly and 670 mg/m2 every 3 weeks. Skin and mucosal toxicities were DLTs. On the basis of responses in metastatic melanoma and SCLC, further investigations in these indications were initiated. Clin Cancer Res; 17(9); 2997–3004. ©2011 AACR.

Randomized Phase II Trial of Gemcitabine Plus TH-302 Versus Gemcitabine in Patients With Advanced Pancreatic Cancer

PURPOSE TH-302 is an investigational hypoxia-activated prodrug that releases the DNA alkylator bromo-isophosphoramide mustard in hypoxic settings. This phase II study (NCT01144455) evaluated gemcitabine plus TH-302 in patients with previously untreated, locally advanced or metastatic pancreatic cancer. PATIENTS AND METHODS Patients were randomly assigned 1:1:1 to gemcitabine (1,000 mg/m(2)), gemcitabine plus TH-302 240 mg/m(2) (G+T240), or gemcitabine plus TH-302 340 mg/m(2) (G+T340). Randomized crossover after progression on gemcitabine was allowed. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, CA 19-9 response, and safety. RESULTS Two hundred fourteen patients (77% with metastatic disease) were enrolled between June 2010 and July 2011. PFS was significantly longer with gemcitabine plus TH-302 (pooled combination arms) compared with gemcitabine alone (median PFS, 5.6 v 3.6 months, respectively; hazard ratio, 0.61; 95% CI, 0.43 to 0.87; P = .005; median PFS for metastatic disease, 5.1 v 3.4 months, respectively). Median PFS times for G+T240 and G+T340 were 5.6 and 6.0 months, respectively. Tumor response was 12%, 17%, and 26% in the gemcitabine, G+T240, and G+T340 arms, respectively (G+T340 v gemcitabine, P = .04). CA 19-9 decrease was greater with G+T340 versus gemcitabine (-5,398 v -549 U/mL, respectively; P = .008). Median OS times for gemcitabine, G+T240, and G+T340 were 6.9, 8.7, and 9.2 months, respectively (P = not significant). The most common adverse events (AEs) were fatigue, nausea, and peripheral edema (frequencies similar across arms). Skin and mucosal toxicities (2% grade 3) and myelosuppression (55% grade 3 or 4) were the most common TH-302-related AEs but were not associated with treatment discontinuation. CONCLUSION PFS, tumor response, and CA 19-9 response were significantly improved with G+TH-302. G+T340 is being investigated further in the phase III MAESTRO study (NCT01746979).

Phase II Study of the Safety and Antitumor Activity of the Hypoxia-Activated Prodrug TH-302 in Combination With Doxorubicin in Patients With Advanced Soft Tissue Sarcoma

PURPOSE TH-302, a prodrug of the cytotoxic alkylating agent bromo-isophosphoramide mustard, is preferentially activated in hypoxic conditions. This phase II study investigated TH-302 in combination with doxorubicin, followed by single-agent TH-302 maintenance therapy in patients with first-line advanced soft tissue sarcoma (STS) to assess progression-free survival (PFS), response rate, overall survival, safety, and tolerability. PATIENTS AND METHODS In this open-label phase II study, TH-302 300 mg/m(2) was administered intravenously on days 1 and 8 with doxorubicin 75 mg/m(2) on day 1 of each 21-day cycle. After six cycles, patients with stable and/or responding disease could receive maintenance monotherapy with TH-302. RESULTS Ninety-one patients initiated TH-302 plus doxorubicin induction treatment. The PFS rate at 6 months (primary efficacy measure) was 58% (95% CI, 46% to 68%). Median PFS was 6.5 months (95% CI, 5.8 to 7.7 months); median overall survival was 21.5 months (95% CI, 16.0 to 26.2 months). Best tumor responses were complete response (n = 2 [2%]) and partial response (n = 30 [34%]). During TH-302 maintenance (n = 48), five patients improved from stable disease to partial response, and one patient improved from partial to complete response. The most common adverse events during induction were fatigue, nausea, and skin and/or mucosal toxicities as well as anemia, thrombocytopenia, and neutropenia. These were less severe and less frequent during maintenance. There was no evidence of TH-302-related hepatic, renal, or cardiac toxicity. CONCLUSION PFS, overall survival, and tumor response compared favorably with historical outcomes achieved with other first-line chemotherapies for advanced STS. A phase III study of TH-302 is ongoing (NCT01440088).

Angiotensin II for the Treatment of Vasodilatory Shock

Background Vasodilatory shock that does not respond to high‐dose vasopressors is associated with high mortality. We investigated the effectiveness of angiotensin II for the treatment of patients with this condition. Methods We randomly assigned patients with vasodilatory shock who were receiving more than 0.2 μg of norepinephrine per kilogram of body weight per minute or the equivalent dose of another vasopressor to receive infusions of either angiotensin II or placebo. The primary end point was a response with respect to mean arterial pressure at hour 3 after the start of infusion, with response defined as an increase from baseline of at least 10 mm Hg or an increase to at least 75 mm Hg, without an increase in the dose of background vasopressors. Results A total of 344 patients were assigned to one of the two regimens; 321 received a study intervention (163 received angiotensin II, and 158 received placebo) and were included in the analysis. The primary end point was reached by more patients in the angiotensin II group (114 of 163 patients, 69.9%) than in the placebo group (37 of 158 patients, 23.4%) (odds ratio, 7.95; 95% confidence interval [CI], 4.76 to 13.3; P<0.001). At 48 hours, the mean improvement in the cardiovascular Sequential Organ Failure Assessment (SOFA) score (scores range from 0 to 4, with higher scores indicating more severe dysfunction) was greater in the angiotensin II group than in the placebo group (‐1.75 vs. ‐1.28, P=0.01). Serious adverse events were reported in 60.7% of the patients in the angiotensin II group and in 67.1% in the placebo group. Death by day 28 occurred in 75 of 163 patients (46%) in the angiotensin II group and in 85 of 158 patients (54%) in the placebo group (hazard ratio, 0.78; 95% CI, 0.57 to 1.07; P=0.12). Conclusions Angiotensin II effectively increased blood pressure in patients with vasodilatory shock that did not respond to high doses of conventional vasopressors. (Funded by La Jolla Pharmaceutical Company; ATHOS‐3 ClinicalTrials.gov number, NCT02338843.)

A Phase I Study of the Safety and Pharmacokinetics of the Hypoxia-Activated Prodrug TH-302 in Combination with Doxorubicin in Patients with Advanced Soft Tissue Sarcoma

Purpose: The purpose of this study was to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), safety, pharmacokinetics and preliminary activity of TH-302, a hypoxia-activated prodrug, in combination with doxorubicin in patients with advanced soft tissue sarcoma. Patients and Methods: TH-302 was administered intravenously on days 1 and 8 and doxorubicin 75 mg/m2 on day 1 (2 h after TH-302) of every 3-week cycle. TH-302 starting dose was 240 mg/m2 with a classic 3 + 3 dose escalation. Pharmacokinetics were assessed on days 1 and 8 of cycle 1. Tumor assessments were performed after every second cycle. Results: Sixteen patients enrolled. Prophylactic growth factor support was added due to grade 4 neutropenia. The MTD was 300 mg/m2. DLTs at 340 mg/m2 were neutropenia-associated infection and grade 4 thrombocytopenia. Common adverse events included fatigue, nausea and skin rash. There was no evidence of pharmacokinetic interaction between TH-302 and doxorubicin. Five of 15 (33%) evaluable patients had a partial response by RECIST (Response Evaluation Criteria in Solid Tumors) criteria. Conclusions: The hematologic toxicity of doxorubicin is increased when combined with TH-302. This can be mitigated by prophylactic growth factor support. Toxicities were manageable and there was evidence of antitumor activity.

Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): An international, multicentre, open-label, randomised phase 3 trial

BACKGROUND Evofosfamide is a hypoxia-activated prodrug of bromo-isophosphoramide mustard. We aimed to assess the benefit of adding evofosfamide to doxorubicin as first-line therapy for advanced soft-tissue sarcomas. METHODS We did this international, open-label, randomised, phase 3, multicentre trial (TH CR-406/SARC021) at 81 academic or community investigational sites in 13 countries. Eligible patients were aged 15 years or older with a diagnosis of an advanced unresectable or metastatic soft-tissue sarcoma, of intermediate or high grade, for which no standard curative therapy was available, an Eastern Cooperative Oncology Group performance status of 0-1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (1:1) to receive doxorubicin alone (75 mg/m2 via bolus injection administered over 5-20 min or continuous intravenous infusion for 6-96 h on day 1 of every 21-day cycle for up to six cycles) or doxorubicin (given via the same dose procedure) plus evofosfamide (300 mg/m2 intravenously for 30-60 min on days 1 and 8 of every 21-day cycle for up to six cycles). After six cycles of treatment, patients in the single-drug doxorubicin group were followed up expectantly whereas patients with stable or responsive disease in the combination group were allowed to continue with evofosfamide monotherapy until documented disease progression. A web-based central randomisation with block sizes of two and four was stratified by extent of disease, doxorubicin administration method, and previous systemic therapy. Patients and investigators were not masked to treatment assignment. The primary endpoint was overall survival, analysed in the intention-to-treat population. Safety analyses were done in all patients who received any amount of study drug. This study was registered with ClinicalTrials.gov, number NCT01440088. FINDINGS Between Sept 26, 2011, and Jan 22, 2014, 640 patients were enrolled and randomly assigned to a treatment group (317 to doxorubicin plus evofosfamide and 323 to doxorubicin alone), all of whom were included in the intention-to-treat analysis. The overall survival endpoint was not reached (hazard ratio 1·06, 95% CI 0·88-1·29; p=0·527), with a median overall survival of 18·4 months (95% CI 15·6-22·1) with doxorubicin plus evofosfamide versus 19·0 months (16·2-22·4) with doxorubicin alone. The most common grade 3 or worse adverse events in both groups were haematological, including anaemia (150 [48%] of 313 patients in the doxorubicin plus evofosfamide group vs 65 [21%] of 308 in the doxorubicin group), neutropenia (47 [15%] vs 92 [30%]), febrile neutropenia (57 [18%] vs 34 [11%]), leucopenia (22 [7%] vs 17 [6%]), decreased neutrophil count (31 [10%] vs 41 [13%]), and decreased white blood cell count (39 [13%] vs 33 [11%]). Grade 3-4 thrombocytopenia was more common in the combination group (45 [14%]) than in the doxorubicin alone group (four [1%]), as was grade 3-4 stomatitis (26 [8%] vs seven [2%]). Serious adverse events were reported in 145 (46%) of 313 patients in the combination group and 99 (32%) of 308 in the doxorubicin alone group. Five (2%) patients died from treatment-related causes in the combination group (sepsis [n=2], septic shock [n=1], congestive cardiac failure [n=1], and unknown cause [n=1]) versus one (<1%) patient in the doxorubicin alone group (lactic acidosis [n=1]). INTERPRETATION The addition of evofosfamide to doxorubicin as first-line therapy did not improve overall survival compared with single-drug doxorubicin in patients with locally advanced, unresectable, or metastatic soft-tissue sarcomas and so this combination cannot be recommended in this setting. FUNDING Threshold Pharmaceuticals.

Abstract LB-121: Randomized phase II study of the efficacy and safety of gemcitabine + TH-302 (G+T) vs gemcitabine (G) alone in previously untreated patients with advanced pancreatic cancer

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL A hypoxic microenvironment is believed to be a characteristic of solid tumors including pancreatic adenocarcinoma (PAC) and is associated with resistance to chemotherapy. The hypoxia-activated prodrug, TH-302, is designed to specifically target the hypoxic microenvironment. Combining G with TH-302 may enable the targeting of both the normoxic and hypoxic regions of PAC. TH-302 was investigated with full-dose G as part of a Phase 1/2 study with a 21% response, median PFS and OS of 5.9 and 8.5 months, respectively, and one-year survival of >40%. Based upon these data, a randomized Phase 2B study ([NCT01144455][1]) was conducted to assess the benefit of G+T to standard dose G for first-line therapy of PAC. An open-label multi-center study of two dose levels of TH-302 (240 mg/m2 or 340 mg/m2) in combination with G versus G alone (randomized 1:1:1) was initiated in June 2010. G (1000 mg/m2) and T were administered IV over 30-60 minutes on Days 1, 8 and 15 of a 28-day cycle. Patients on the G arm could crossover after progression and be randomized to a G+T arm. The primary efficacy endpoint is a comparison of progression-free survival (PFS) between the combination arms and G alone (80% power to detect 50% improvement in PFS with one-sided alpha of 10%). 214 pts (69 G: 71 G+T240: 74 G+T340) with advanced PAC including 77% distant metastases, 62% involving liver and 11% with prior adjuvant tx; median age: 65 (range 29-86); 126 M/88 F; 79/128 ECOG 0/1. Median cycles received: G - 4, G+T240 - 5, G+T340 - 6. Median PFS was 3.6 mo in G vs 5.6 mo in G+T arms with HR of 0.61 (95% CI: 0.43 - 0.87) and logrank p-value of 0.005. Median PFS in G + T340 was 6.0 mo. RECIST best response was 12% in G, 17% in G+T 240 and 27% in G+T340. 153 (71%) patients had elevated CA19-9 and follow-up. CA19-9 decreases were significantly greater in the G+T groups and greatest in the G+T340 arm which had 37 of 53 (70%) pts with a greater than 50% CA19-9 decrease. One death (suicide) was considered possibly related to study drug. Adverse events leading to discontinuation were: 16% G, 15% G+T240 and 11% G+T340. Serious adverse events were balanced across the treatment arms. The most common non-laboratory events, fatigue (49%), nausea (43%), constipation (34%) and peripheral edema (38%), were similar across groups. Rash (14% G, 39% G+T240 and 45% G+T340) and stomatitis (6% G, 17% G+T240 and 36% G+T340) were significantly greater with G+T combination but no Grd 4 (4 pts with Grade 3). Grd 3/4 thrombocytopenia (11% G, 39% G+T240 and 59% G+T340) and Grd 3/4 neutropenia (28% G, 56% G+T240 and 59% G+T340) were higher with G+T. G+T combination with full dose G improved the efficacy of G with significantly longer PFS, higher response rate and greater CA19-9 declines. The G+T combination was well tolerated. Skin and mucosal toxicity and myelosuppression were the most common related adverse events with no increase in treatment discontinuation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-121. doi:1538-7445.AM2012-LB-121 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01144455&atom=%2Fcanres%2F72%2F8_Supplement%2FLB-121.atom

Abstract A34: Hypoxia-activated prodrug TH-302 in combination with gemcitabine for the treatment of pancreatic adenocarcinoma: Preclinical and clinical studies.

Hypoxia is a prevalent feature of solid tumors and is a negative prognostic factor associated with treatment failure and the emergence of a more aggressive, invasive, and metastatic phenotype. Hypoxia in human pancreatic adenocarcinoma (PAC) has been characterized by Eppendorf needle oxygen electrodes, and more recently by the use of the exogenous hypoxia biomarker pimonidazole in patient biopsies. Both methods have demonstrated significant subregional hypoxia. TH-302 (T) is a hypoxia-activated bioreductive prodrug that is selectively activated in regions of severe hypoxia, and upon activation releases the bis-alkylating DNA cross-linker bromoisophosphoramide mustard (Br-IPM). T exhibits hypoxia-selective in vitro cytotoxicity across a wide panel of human cancer cell lines including PAC cell lines and in vivo anti-tumor efficacy in a range of human tumor models including a PAC orthotopic model. T is currently under investigation in multiple oncology clinical trials. A panel of human PAC human tumor xenograft models were established (Hs766t, SU.86.86, BxPc3, MIA PaCa2) and tested with gemcitabine (G) and T both as monotherapies and in combination (G+T) for antitumor efficacy. Select tissue biomarkers, focused on characterizing the magnitude and extent of tumor hypoxia, tumor vascularity, and EMT and G resistance/sensitivity phenotypic markers were assessed by IHC and compared with the corresponding drug efficacy profiles observed in the models. Initial clinical study of G+T combination was a phase 1/2a trial with G administered at its full labeled dose and schedule (1000 mg/m 2 on days 1, 8, and 15 of a 28 day cycle) and T dose escalated starting at 240 mg/m 2 in combination with G with the same schedule (T administered 2 hr before G). An expansion phase 2a portion of the trial explored both 240 and 340 mg/m 2 T in combination with G (n=47 pts). A 21% response rate (RR), median PFS and OS of 5.9 and 8.5 mo, and one-yr survival of >40% was observed. These promising results led to initiation of a randomized controlled Phase 2b trial (G vs. G+T240 vs. G+T340). This trial had 80% power to detect 50% improvement in the primary endpoint of PFS with one-sided alpha of 10%. 214 pts were treated across the three arms (~1:1:1). Primary efficacy endpoint was met with a median PFS of 3.6 mo in G arm vs. 5.6 mo in G+T arms with HR of 0.61 (95%CI: 0.43-0.87; logrank p-value of 0.005). Median PFS in G+T340 was 6.0 mo. RR was 12% in G, 17% in G+T240 and 27% in G+T340. Decreases in circulating PAC biomarker CA19-9 were greater in G+T groups than in the G group and greatest in G+T340. G+T was well-tolerated with skin and mucosal toxicities and myelosuppression the most common TH-302 related AEs with no increase in discontinuations for AE. SAEs were balanced across the three arms. These studies of safety and activity of TH-302 in combination with gemcitabine are consistent with the novel design and hypoxia selective characterization of TH 302. Animal and human studies indicate that TH-302, a tumor hypoxia targeting prodrug, can significantly improve the activity of chemotherapy. Citation Format: Charles P. Hart, Jessica D. Sun, Qian Liu, Dharmendra Ahluwalia, Clarence Eng, David P. Ryan, Mitesh J. Borad, Stew Kroll. Hypoxia-activated prodrug TH-302 in combination with gemcitabine for the treatment of pancreatic adenocarcinoma: Preclinical and clinical studies. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr A34.