Promising TH-302 Results Accelerate Sarcoma Study

William D. Tap, MD

Section Chief, Sarcoma Oncology

Melanoma and Sarcoma Services

Memorial Sloan-Kettering Cancer Center

New York, NY

The list of agents currently available to treat soft-tissue sarcoma is rather short, with no drugs being approved on the basis of an improvement in overall survival in approximately 20 years. However, a new agent called TH-302 has not only yielded positive phase II data, but its phase III study also has recently been expanded to include more patients to meet the enrollment demand.

The clinical trial milestone is particularly notable, since only about 11,410 new cases of soft-tissue sarcoma are likely to be diagnosed in the United States in 2013, according to the American Cancer Society. It also has been difficult for researchers to develop therapies that can apply to all patients with sarcoma, not just those with specific types of tumors, such as gastrointestinal stromal tumors (GISTs).

“The issue with sarcoma is that it’s really not one group of malignancies,” said William D. Tap, MD, section chief of Sarcoma Oncology in Melanoma and Sarcoma Services at Memorial Sloan-Kettering Cancer Center. “Depending on the source of the textbook you go to, there are over 50 to 80 different types of sarcoma, and they run the gamut from really benign, indolent types of tumors to very, very aggressive malignancies.”

Tap also explained that there is significant genetic variability within subtypes of sarcomas; they can develop in almost any part of the body, including blood vessels, muscle tissue, bone, fat tissue, or nerves; and they can affect patients of almost any age.

However, one factor that many of these tumors have in common is hypoxia, or areas of low oxygen in a tumor. Research has found that subregional hypoxia in tumors often leads to the failure of treatment options such as chemotherapy and radiotherapy.

“Historically, that’s always a difficult area to target with systemic therapies, the thought being that systemic therapies can profuse more adequately into those areas of the tumors that actually have a good blood supply,” said Tap. He said a therapy “can profuse probably a little bit out of the vasculature, but it doesn’t really penetrate into areas where there’s not a great blood supply.”

Tap said that studies have shown that more extensive hypoxia can be associated with worse outcomes in multiple types of cancer, since these areas can serve as “sanctuaries” for cancer cells, and that additional research has shown that sarcomas tend to have significant areas of hypoxia. Therefore, a drug that targets these areas of the tumor might be able to work in tandem with cytotoxic therapy to more successfully kill tumor cells.

TH-302 is an investigational agent developed by Threshold Pharmaceuticals as a prodrug that is selectively activated when subjected to hypoxic conditions in tumors. Once it reaches these areas, it is converted into its active form, bromo isophosphoramide mustard (Br-IPM). Tap said isophosphoramide is one of the most effective agents against sarcoma.

A phase II trial already has yielded encouraging data, with updated results being presented at the 17th annual meeting of the Connective Tissue Oncology Society (CTOS), which took place last November in Prague, Czech Republic. In the single- arm study, 91 previously untreated patients with metastatic or locally advanced unresectable soft-tissue sarcomas received TH-302 (300 mg/m2 on days 1 and 8 of a 21-day cycle) and doxorubicin (75 mg/m2 on day 1) for a maximum of six cycles. Patients with stable disease or those who achieved partial or complete responses with acceptable toxicity after these six cycles were eligible to receive maintenance therapy with the same dose.

The study found that the median progression-free survival (PFS) was 6.7 months (95% CI, 6.2-8.1) and the median overall survival (OS) was 21.5 months (95% CI, 16.0-27.6). The one-year survival rate was 73% (95% CI, 63%—82%), and the two-year survival rate was 44% (95% CI, 32%–55%). While these patients were not compared with another arm, Tap said the results are encouraging, and that the median PFS and OS rates obtained in the study are higher than what studies have shown when similar patients have received doxorubicin alone. Van der Graaf et al reported at the European Society for Medical Oncology (ESMO) 2012 Congress that patients with soft-tissue sarcoma who received doxorubicin alone in a phase III trial achieved a median PFS of 4.6 months and an OS of 12.8 months.

The most commonly reported adverse events (AEs) were nausea (70%) and fatigue (67%). Reversable grade 1/2 AEs included skin rash (32%), hyperpigmentation (18%), and stomatitis (41%). Grade 3/4 AEs included neutropenia (20%) and thrombocytopenia (25%). There was no evidence of renal, hepatic, or cardiotoxicity.

A phase III study, TH-CR-406, is already under way, but Threshold recently announced that the trial is being expanded for several reasons. The study is enrolling patients faster than anticipated, so the cohort is being expanded from 450 patients to 620 patients. This will allow the study to determine whether an improvement in OS can be seen, with a goal of 16 months in the treatment arm compared with 12 months in the control arm (Figure).

Figure. Phase III THC-302 Trial in Soft-Tissue Sarcoma

Br-IPM indicates bromo isophosphoramide mustard; ECOG, Eastern Cooperative Oncology Group.

Source: NIH Clinical Trials Registry, www.clinicaltrials.gov. NCT01440088.

Plans for an interim futility analysis were canceled after the patient population was expanded with the FDA’s consent because enrollment would have been nearly complete before the analysis was finished, said Tap. An independent data monitoring committee will still be used to analyze safety. Tap said he is hopeful that the trial will give investigators additional promising information regarding TH-302.

“It’s important at this stage to understand that doxorubicin in most clinicians’ minds still remains the gold standard, and the study is designed to see how the combination holds up against doxorubicin,” Tap said. “To really have a breakthrough with cytotoxic agents for patients with sarcoma would be tremendous.”