2.4 Performance-in-Service
2.4.3 Performance-in-Service: in vivo (Canine and Human Clinical Trials)
esophageal and cervix cancer has been measured and estimated to be in the range of 90–160mm, respectively.105Thus, Dox-LTSL can, on average, deliver doxorubicin to nearly every tumor cell, since the penetration distance is over 70mm and drug would be delivered from both sides of a tumor core.105 Of course, these are average values and heterogeneity in delivery is not taken into account. The important point is whether the drug reaches all tumor cells in a concentration adequate to kill them. That is not yet known.
2.4.3 Performance-in-Service: in vivo (Canine and Human
ThermoDoxsviathermal microwave therapy in patients with adenocarcinoma of the prostate. The trial was terminated in 2009 and data were not released.
The primary liver cancer Phase I trial111was initiated in February 2007 and completed accrual by December 2009. It has now advanced to a Phase III (see below). Primary liver cancer is one of the most deadly forms of cancer and ranks as the fifth most common solid tumor cancer. The incidence of primary liver cancer today is approximately 26,000 cases per year in the United States, approximately 40,000 cases per year in Europe and is rapidly growing worldwide at approximately 750,000 cases per year, 55% of which are in China, due to the high prevalence of Hepatitis B and C. The World Health Organ- ization estimates that primary liver cancer may become the number one cancer worldwide, surpassing lung cancer, by 2020. The standard first-line treatment for liver cancer is surgical resection of the tumor; however, 90% of patients are ineligible for surgery. Radio Frequency Ablation (RFA) has increasingly become the standard of care for non-resectable liver tumors, but the treatment cannot adequately ablate larger tumors. There are few non-surgical therapeutic treatment options available, as radiation therapy and chemotherapy are largely ineffective in the treatment of primary liver cancer.
While single-agent doxorubicin has been found to be effective, it has not become a standard treatment for HepatoCellular Carcinoma (HCC) due to its relatively high incidence of severe toxicity, including congestive heart failure and neutropenia. Hence the new initiative to increase the HCC cure rate by combining two approaches: ThermoDoxs with Radio Frequency Ablation (RFA). The ThermoDoxs Phase I study111 was a multi-center, open label, single dose, dose escalation study, to evaluate tolerability of ThermoDoxsin patients with liver tumors undergoing Radio Frequency Ablation.113Patients with unresectable liver cancers underwent RFA with a 30-min. i.v. infusion of ThermoDoxs starting 15 min. before RFA. The aims were to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Clinically, radio-frequency ablation inducesin situthermal coagulation necrosis through the delivery of high-frequency alternating current to the tissues. However, RFA is limited.114With currently available devices, the largest focus of necrosis that can be induced with a single application is approximately 4–5 cm in greatest diameter and lesions that size have a high frequency of marginal recurrences.
Thus, the diameter of suitable lesions must be less than 3–4 cm. Further, tumors located near large vessels may not be effectively ablated because the heat sink effect of these vessels prevents ablation temperatures from being reached. It is these two scenarios that ThermoDoxs is ideal for, because the temperature necessary to cause drug release (411C) is over 151C lower than the ablation temperature (4551C). As shown in Figure 2.20 the placement of an RFA electrode in a liver tumor can produce temperatures in the ablation zone upwards of 601C.
It is here that as the ablation temperature drops off (in the range 501C–391C that, as we saw earlier in itsin vitroperformance (Figure 2.14),46ThermoDoxs can release its drug at significant rates, and deposit high concentrations of doxorubicin in the heated zone.
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The objective of the Phase I study was to determine the maximum tolerated dose (MTD) of ThermoDoxs when used in combination with Radio Frequency Ablation (RFA) in the treatment of primary and metastatic tumors of the liver.111,112As reported by Poonet al.113a total of 24 patients (9 with HCC and 15 with metastatic liver cancer (MLC)) were treated (3, 6, 6, 6, 3 patients at 20, 30, 40, 50 and 60 mg/m2, respectively). Median tumor size was 3.7 cm (range 1.7–6.5 cm). In total, 28 tumors were treated. Twenty (83%) of the patients had no evidence of local tumor failure after treatment. Despite this only being a Phase I dose escalation toxicity study, as shown in Figure 2.21 there was a dose-response relationship in terms of time to tumor progression (of 32, 53, 135, 185 days, respectively), giving aB500% increase in progression free survival for the MTD (50 mg/m2) compared to the lowest starting dose.
Figure 2.20 Radio Frequency Ablation of liver tumors.
Figure 2.21 Results for Phase I dose escalation study to determine maximally tolerated dose for ThermoDoxsin conjunction with Radio Frequency Ablation in the treatment of hepatocellular carcinoma (HCC). Dose responsevs.time for tumors to progress.
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Encouragingly, then, there appeared to be a preliminary dose response relationship in terms of time to tumor progression as the study reached its maximally tolerated dose.
2.4.3.3 Phase III Studies: HepatoCellular Carcinoma (HEAT)
Given the efficacy seen in this Phase I trial, clinical testing was moved rapidly to a Phase III, randomized, double-blinded, dummy-controlled study of the efficacy and safety of ThermoDoxs in combination with Radio Frequency Ablation (RFA) compared to RFA-alone in the treatment of non-resectable hepatocellular carcinoma.115This so-called HEAT study engaged 71 different sites in 11 different countries, and is the largest study ever conducted in intermediate hepatocellular carcinoma. It is looking to treat the usually untreatable large 3 cm–7 cm tumors. It is being conducted under a US Food and Drug Administration (FDA) Special Protocol Assessment, has received FDA Fast Track Designation and has been designated as a Priority Trial for liver cancer by the National Institutes of Health. ThermoDoxs has been granted orphan drug designation in both the US and Europe for this indication.
The European Medicines Agency (EMA) has confirmed the HEAT study is acceptable as a basis for submission of a marketing authorization application (MAA). In addition to meeting the US FDA and European EMA enrollment objectives, the HEAT study has also enrolled a sufficient number of patients to support registration filings in China, South Korea and Taiwan, three other large and important markets for ThermoDoxs.
The arms of the study are:
Experimental 1: ThermoDoxs(50 mg/m2in 5% dextrose solution). Start 30 minute infusion about 15 minutes before radio frequency ablation begins.
Sham Comparator 2: Sham (5% dextrose solution). Start 30 minute infusion about 15 minutes before radio frequency ablation begins.
The Primary Outcome Measures are:
Progression-free survival will be measured from the date of randomization to the first date on which one of the following occurs. (a) Local recurrence, (b) any new distant intrahepatic HCC tumor, (c) any new extrahepatic HCC tumor, (d) death from any cause (time frame: 3 years). A secondary confirmatory endpoint is overall survival.
The Main Inclusion Criteria are:
Diagnosed hepatocellular carcinoma (HCC).
No more than 4 HCC lesions with at least oneZ3.0 cm and none47.0 cm in maximum diameter, based on diagnosis at screening.
If a subject has a large lesion (5.0–7.0 cm), any other lesions must be o5.0 cm.
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As of May 2012, the HEAT study reached its enrollment objective of 700 patients. The primary endpoint for the study is to measure a 33% improvement in progression-free survival (PFS), with a P value of 0.05. A total of 380 events of progression are required to reach the planned final analysis of the study. 380 PFS events are projected to occur in late 2012. While the data are not at the moment available, there is an interesting comparison that can be made between the dose response seen in the Phase I study and the criteria for this Phase III.
As mentioned above, the PFS in the Phase III study is required to show only a 33% improvement compared to RFA alone. This compares very favorably with the increase in PFS in Phase I seen for the dose escalation (from 20 mg/m2–50 mg/m2) of almost 500% (the RFA-alone control was not done).
While no firm conclusions should be taken from such a limited set of data (and this is indeed the reason a 700-patient multi-center trial is in fact required to obtain useful statistics), it is interesting to compare these two %PFS increase numbers. Also, a second caveat is that in the Phase I trial, median tumor size was 3.7 cm (range 1.7–6.5 cm), which although not the same, is not substantially different, compared to the criteria for the Phase III: ‘‘No more than 4 HCC lesions with at least oneZ3.0 cm and none47.0 cm in maximum diameter.’’
2.4.3.4 Phase I/II Trial Breast Cancer Recurrence at the Chest Wall (RCW) (DIGNITY Study)
A second human Phase I/II trial, this time in breast cancer,116was designed to evaluate the maximum tolerated dose, pharmacokinetics, safety and efficacy of approved hyperthermia and ThermoDoxs in patients with breast cancer recurrence at the chest wall (DIGNITY study). The purpose of this study is to evaluate the bioequivalence of ThermoDoxsand measure efficacy in recurrent chest wall patients. In the initial Phase I (which was actually started in 2001, but later became non-recruiting117), there were several instances of stable disease, partial response and two of complete responses for a dose escalation of 20 mg/m2–30 mg/m2. As reported by Vujaskovic,118several patients in this trial achieved either partial or complete responses. As shown in Figure 2.22, for one
A B
Baseline Precycle 5
Figure 2.22 Treatment of chest wall recurrence of breast cancer, using a BSD-500 PC System to achieve a temperature goal of 40–421C (A) and same patient before treatment and pre-cycle 5 (B).
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patient, her widely disseminated chest wall tumor had completely disappeared.
This test dose (30 mg/m2) was only 60% of the expected maximally tolerated dose, and so there were no side effects of the drug. A second patient had a similar complete response at 30 mg/m2.118
The Phase I/II DIGNITY trial studying ThermoDoxs for breast cancer116 has now continued the study in several sites and has demonstrated remarkable clinical benefit in a very late-stage, underserved patient population. As presented at the European Society of Medical Oncology (EMO) conference 2012,119the clinical utility of ThermoDoxs in this highly treatment-resistant setting points to its potential within a variety of superficial tumors, and could provide medical oncologists with an important tool to combat these often aggressive tumors. According to the lead clinician, the initial experience with hyperthermia and ThermoDoxs has been very encouraging and provides initial safety and early efficacy data in several patients showing responses in this highly refractory and debilitating disease. These patients previously received over an average of four prior chemotherapy regimens along with prior radiation therapy. The continuation of the ThermoDoxs trial will provide more efficacy data to potentially advance treatment for this patient population.
2.4.3.5 Phase II Colorectal Liver Metastases ABLATE
The third and final on-going human trial is a randomized, double blind, Phase II trial of RFA þ/– ThermoDoxs for Colorectal Liver Metastases Z2 cm maximum in diameter.120 Again, the purpose of this study is to determine the safety and efficacy of ThermoDoxs, in combination with RFA in the treatment of recurrent or refractory colorectal liver metastases compared to RFA mono-therapy. The primary outcome of this trial is to evaluate local tumor control defined as complete ablation and where the patient does not experience recurrence within 1 cm of the ablation site.