Clinical Experience with LTSL-Dox
Celsion's Clinical-Trials Experience with ThermoDox and Hyperthermia Technologies and Where We Go From Here
Here, we briefly review the three main cancers Prostate, Recurrent Chest Wall (RCW) and Primary Liver (HepatoCellular Carcinoma, HCC) that Celsion trialed LTSL-Dox as Thermodox in. These trials showed that:
Prostate Cancers could be warmed to sufficient temperatures by the prostate-heating Prolieve Technology and a safe LTSL-Dox dose could be achieved at 50mg/m^2; there were even some very positive remissions;
Recurrent Chest Wall cancer also showed positive data with some cures at only 30mg/m^2 using a chest BSD 500 heat applicator; and
Primary Liver Cancer in Phase I and then two Phase III trials, showed some significant Progression Free Survivals, especially in a subgroup analysis.
Even though Thermodox was not quite approved, and some reasons are given below, we feel that it is important to present and briefly review this data on other cancers for at least 3 reasons:
1. Dosing levels have already been established shown to be safe in ~2,000 patients.
2. It provides compelling evidence that, if heating technologies like LITT can warm the tumor, then LTSL-Dox will rapidly release its drug in the brain tumor periphery.
3. While treating these other tumors were not pursued these decisions were not made because the technology didn't work.
4. They also represent additional cancers that can also be treated with LTSL-Dox if we have the will and can find the way. In fact, all cancers that can be warmed by any effective hyperthermia device that can achieve 41-42°C in the tumor tissue could, in principle, be treated and so represent additional applications of this innovative and effective drug delivery technology.
(Top) Schematic of the Prolieve (balloon catheter) Technology for Benign Prostate Hyperthermia (BPH)
(Bottom) Measured temperatures in the heated prostate showing that the Prolieve technology could warm to 42°C at the edge ensuring that doxorubicin was released from LTSL-Dox throughout the prostate tumor.
Prostate Cancer (2003 - 2005) (Prolieve Balloon Catheter)
By June 5th 2003 a Phase I (dose escalation) trial was started in Prostate Cancer (see Clinical Trials.gov, (1)). In this study, the prostate and its cancer was heated by the Prolieve TransUrethral Microwave Thermotherapy (TUMT) device to warm the whole prostate. This device was actually developed for Benign Prostate Hyperthermia (BPH) by Medifocus. In the Phase I study, dose escalation from 20mg/m^2 to 55 mg/m^2 showed that Thermodox was safe at a treatment of 50mg/m^2. In unpublished data, it was even shown to have some efficacy (see below, Prostate Map). As demonstrated in the diagrams to the left, this Prolieve technology could therefore warm the whole prostate out to at least 42°C at the edge and so was capable of releasing doxorubicin from the LTSL-Dox throughout the whole prostate tumor.
So why was this not advanced beyond Phase I in 2005? Unfortunately, despite the successful Phase I trial, this application of Thermodox and Prolieve technology was abandoned by Celsion apparently because of an already crowded Prostate market.
(1) Liposomal Doxorubicin and Thermal Therapy in Treating Patients With Prostate Cancer
Recurrent Chest Wall Cancer (2006 - 2014) (BSD ChestWall Applicator)
Then in 2006 – 2007 a Phase I study of Thermodox in Recurrent Chest Wall Cancer (cancers that grow on the chest wall after mastectomy) was carried out at Duke, --see the paper by Zagar et al (1). Here, HT was administered for 1 hr using a BSD-500 PC System. With Thermodox in the patient's blood stream administered by intravenous infusion, warming the chest wall tumors to just 40–42°C gave 48% (14/29) Local response; 31% partial response (9/29); and 17% Complete Response (5/29). Top image shows a picture of a patient receiving the treatment. Bottom images are photographic pictures of her chest wall cancer at Baseline, and after four cycles of 1hr HT + Thermodox; the cancer was completely cured. What's more, the dose here was only 30mg/m^2 and so less than the therapeutic dose of 50mg/m^2 that was eventually-found-to-be-safe. This first trial was followed by a Phase I/II (DIGNITY) trial in 2009-2017, (see clinical trials.gov)
Again, though, why was this successful Phase I/II not advanced and continued for FDA approval? It appears that Thermodox for CWR was also abandoned because of too few cases.
The Choice of Primary Liver Cancer and RFA: Lessons Learned
With an estimated 1M cases of Primary Liver Cancer, (or Hepatocellular Carcinoma HCC) is currently the second most common cause of cancer-related death worldwide. However, as summarized by Lencioni (1), "complete tumor eradication achieved by RFA alone is less than 50% in tumors exceeding 3 cm in diameter resulting in recurrence". Given that Image-guided radiofrequency ablation (RFA) is established as the first-line therapy for nonsurgical patients with early-stage HCC there was reason to believe at the time that RFA ++ Thermodox could show efficacy in these underserved patients.
As we describe below (Some Possible Reasons...) , while there were certainly sub group successes in both the HEAT and OPTIMA studies, approval was not quite achieved for a number of reasons.
It is therefore incumbent on us to review these studies with RFA and the obtained data, so that we can learn from the positives and any mistakes so that this LTSL-Dox technology can be used successfully, safely and efficaciously in brain cancer patients.
RFA Procedure
The thinking was that, as shown in this schematic of a heated liver tumor, RFA could ablate the center of the tumor and perhaps provide some warming of the periphery where the micro-metastases are, and that are the main source of relapse. However, while RFA ablates the tumor visualized in the ablation zone, for tumors bigger than a few centimeters, the heat is unlikely to extend out to the 3cm - 7cm tumor diamaters, and it misses the micro-metastases. As such it probably did not achieve the 42C at the periphery to activate the i.v. LTLSL-Dox to release their doxorubicin in this micrometastatic peripheral thermal zone.
A recent (2017) theoretical and in vivo analysis by the Dieter Hammerich lab (1) showed that, "tissue drug uptake directly correlates with heating duration for TSL based delivery" and that a significant 7.1 μg/g (~22uM) of doxorubicin could be achieved in pig livers by just a 12 min RFA heating. Furthermore, with a visible coagulation zone of ~1 cm diameter, the extent of doxorubicin deposition extended to a further 1.2 cm from the edge of that ablation zone. As used in the HEAT and OPTIMA studies, RFA was applied for 45 mins and so, while there could have been successful treatment for 3cm tumors, heat dissipation due to cooling of blood flow perfusion could have limited the peripheral warming of larger tumor.
This will be a similar question for us to establish for LITT, i.e., what size tumors can it heat effectively to 42C?
(1) Rossmann, C., et al., Temperature sensitive liposomes combined with thermal ablation: Effects of duration and timing of heating in mathematical models and in vivo. PLoS One, 2017. 12(6): p. e0179131.
HEAT Study Kaplan-Meier survival estimates: Overall survival in solitary lesion and RFA dwell time 45 min, n = 285 (from Borys and Dewhirst, (3)
Primary Liver Cancer Phase I Study, Phase III HEAT Study, and Phase III Optima Study (ThermoDox + RadioFrequency Ablation (RFA)) (2004 - 2020)
Phase I Study (2004-2008)
A Phase I dose escalation study in Primary Liver Cancer (HCC) and Metastatic Liver Cancer (MLC) was started in 2007 thru 2009 (1). It achieved a very successful 185 day progression free survival at a Thermodox dose of 50mg/m^2. The Phase I results*, showing increasing time to progression (days) as a function of dose during the escalation trial, were highly suggestive of clinical activity.
And data from a second confirmation study**, in primary and metastatic liver cancer was suggestive of actual local control. For a median follow up time of Ave 5.5 months (3-14), recurrence was only seen in 2 of 44 treated lesions (4.5%). Moreover, for the 10 patients evaluable, there were 5 Complete Responses (50%), 1 Partial Response (10%) and 4 Progressive Disease (Liver ± Lung, 40%)
And so there was considerable optimism that Thermodox + RFA could perhaps effectively treat liver tumors.
* Phase I data presented at IHBA conference, Mumbai India, February 2008
**Phase I data presented by Dr T. S. Ravikumar at WCIO conference, Los Angeles CA, June 2008.
Phase III HEAT Study (2008 – 2013)
The subsequent Phase III HEAT study (1, 2) was the largest HCC study then performed; it started in 2008 and ran through 2013 at 71 sites in 14 different countries and included 701 patients. The heating technology here was again RadioFrequency Ablation, with high ablation temperatures near the probe, getting radially cooler with distance into the tumors.
The protocol was: ThermoDox 50 mg/m^2 start infusion over 30 minutes about 15 minutes before radiofrequency ablation begins. The total length of the RFA procedure was proportional to the size of the tumor(s) involved and was anticipated to range from 12 to 60 minutes for each lesion.
As described by Borys and Dewhirst (3), "Eligible subjects had to be newly diagnosed with hepatocellular carcinoma (HCC) with up to 3 nodules with at least one 3.0 cm and not surgical candidates. Randomization was stratified by lesion size (3–5 cm, >5–7 cm). Patients received a 30-minute intravenous infusion of either 50 mg/m^2 of LTLD or a dummy infusion of D5W. RFA began at15 minutes after starting the infusion and was completed within 3 h."
Unfortunately, in January 2013 Celsion published a press release reporting that, "....the HEAT Study did not meet the goal of demonstrating persuasive evidence of clinical effectiveness that could form the basis for regulatory approval in the population chosen for study. The HEAT Study was designed to show a 33% improvement in PFS with 80% power and a p-value = 0.05. In the trial, ThermoDox® was well-tolerated with no unexpected serious adverse events".
The study found (3) that adding LTSL-Dox to RFA is safe, with reversible neutropenia and leukopenia as the most common toxicity and serious adverse events being rare. With multiple sites involved and at least two different RFA catheters used, the primary end point of progression free survival (PFS) improvement from adding LTSL-Dox to RFA vs RFA alone was not met. (Median PFS was 13.9 months and 14.0 months respectively) and Median OS was 53.4 months in RFA mono-therapy and 53.7 months in RFA + LTSL-Dox.
Subgroup Data Showed Significant Improvement
On the positive side, in 2016 Celsion announced final overall survival data from HEAT study that "Subgroup Data Continue to Show a Statistically Significant Improvement in Overall Survival, Consistent With a Two Year Median Survival Benefit Following Treatment with ThermoDox® plus Optimized RFA"
Interestingly, as shown in the Kaplan Meier plot to the left, a large subgroup of patients (n = 285) with, (importantly) a solitary lesion and a RFA dwell time of >45 min demonstrated an improvement in Overall Survival and PFS with median time to progression of over 23 months in the LTLD + RFA subgroup versus 17 months in the RFA alone subgroup (but not statistically significant (HR of 0.78). From post hoc analysis, this subgroup appears to have done better due to the long (>45 minutes) duration of thermal dose and hence increases drug uptake, inhibits DNA-damage repair pathways and reverses drug resistance.
Phase III OPTIMA Study (2014 – 2020)
And so this prompted the company to pursue an optimized protocol (45 mins) (in 601 patients) in the Primary Liver Phase III "OPTIMA" Study. The official title was: A Phase III, Randomized, Double Blind, Dummy-Controlled Study of ThermoDox® (Lyso-Thermosensitive Liposomal Doxorubicin-LTLD) in Hepatocellular Carcinoma (HCC) Using Standardized Radiofrequency Ablation (RFA) Treatment Time ≥ 45 Minutes for Solitary Lesions ≥ 3 cm to ≤ 7 cm"
We are waiting for the official analysis and announcement, but a press release in 2020 reported that the "Data Monitoring Committee (DMC) recommended that Celsion should consider stopping the OPTIMA Study. Finding that the pre-specified boundary for stopping the trial for futility of 0.900 was marginally crossed with an actual value of 0.903". The study in China and Vietnam showed an unexpected turn, that unfortunately coincided with the advent of COVID19.
Some Possible Reasons for the Less-Than Optimization of RFA + Thermodox?
Thus, while subgroup analysis showed very positive data (285 out of the 701 patients in the trial) overall the HEAT study did not quite meet the required PFS endpoint. This could be due to a range of factors. As delineated by Dou et al (1), potential reasons for failure of the HEAT trial started with a poor choice of liver tumor for Doxorubicin, since HCC has relatively low sensitivity to doxorubicin (although given the amount of dox that can be delivered to cancer cells from Thermodox (~50uM) this might not be such an issue). Depending on the ablation temperature, RFA is known to cause charring of the tissue. Since carbon is an insulator, such charring could have limited the thermal diffusion and is another reason for "turning down the heat" as Allen et al suggest (1). Also, additional doses of ThermoDox® could have improved the clinical outcome. While OS could have shown better efficacy, PFS was chosen as the (faster) primary end point. Results were compromised by local recurrence, distant intra-hepatic and extra-hepatic disease progression, and protocols were not standardized across all 701 patients, 71 sites, in 14 different countries. Then, when the trial was repeated, as above, unfortunately the OPTIMA study showed an unexpected turn for the worse, that apparently coincided with the early cases of COVID19 in the study-sites in China and Vietnam.
One of the biggest problems in treating HCC (like brain cancer) is the recurrence of disease at the treatment margins. For RFA, tumor sizes greater than 3 cm have a greater chance of local recurrence. Thus, in the Celsion trials tumors were 3–5 cm, and >5–7 cm, and so many were outside RFA's ability to warm the margins and so did not achieve the critical 41-42°C necessary to release doxorubicin. Also, given the RFA equipment and modality used, where the main goal is to ablate a central region, there was a lack of real-time feedback on the thermal dose estimation of the whole tumor mass. Thus, for many of the tumors tested (often multiple tumors in a given liver of various sizes), it seems to have been a case of "Heat and Hope". We have seen in the Manzoor study (2) that in the absence of applied heat, LTSL-Dox performed actually worse than free doxorubicin, because there was little, if any, bioavailable drug entering the tumor.
This is where LTSL-Dox and LITT were made for each other.
With the advances in LITT, including its real time thermometry, control over the position of the end fire laser and the rotation of the side-fired laser, the exquisite nature of the thermally triggered drug release at 41-42°C can be well-accommodated. The surgeon can now "Heat and Know". It's now a matter of selecting the right sized and heatable tumors where the peripheral temperature is expected to be met by the LITT technology in primary, recurrent, and also metastatic tumors that could be detected earlier, and so be smaller and more amenable to LITT + LSTL-Dox.
Nevertheless, Thermodox is an extremely well-trialed technology and ready to be trialed in Brain Cancer
A recent analysis by Chaudhry et al et al in their paper Thermosensitive liposomes: a promising step toward localised chemotherapy identified 12 human clinical trials that have investigated the use of Lyso-Thermosensitive Liposomal Doxorubicin (1) (An adapted list with ClinicalTrials.gov Identifier number and acronym, is available here).
These clinical trials include:
All clinical phases, (Phase I, I/II, II and III),
use of different modes of heating (RFA, HiFu, Microwave Ablation (MWA), Radiation Therapy, and MR-HiFu) and
a range of different cancers, (HepatoCellular Carcinoma (HCC), Primary or Secondary Liver Tumors, non resectable, Non-Resectable HCC, Local-Regional Recurrent and Relapsed Breast Cancer, Metastatic Colorectal Cancer (mCRC) Liver Lesions, Local-Regional Relapse in Breast Cancer, Relapsed or Refractory Solid Tumors, Bone Metastases, and primary Pancreatic Tumors.
It should therefore be noted that Thermodox plus HT is an extremely well-studied and applied technology in humans and has been trialed in probably ~ 2,000 people already, and so its safety (at 50mg/m^2) and some definite efficacy have been well-established. This is all due to Celsion's exceptional commitment to this technology, especially the tireless efforts of Mike Tardugno, the ex-CEO and President for over 17 years, (raising over, an impressive, $500M) and Nick Borys, CMO, leading the clinical studies. This is a drug technology that only just narrowly missed receiving FDA Approval in 2012 and, due to some unfortunate and unforeseen circumstances, the subsequent OPTIMA trial, was closed in 2020. And, as we suggest with the LITT heating and thermal monitoring system, the LTSL-Dox could be a potential standard of care for some brain cancers when now tested for safety and efficacy.
The Musella Foundation and the Promising Pathway Act
Given its positive subgroup data in the Primary Liver trials and the positive data in Prostate and Recurrent Chestwall, Thermodox is a perfect candidate for Al Musella's efforts to rescue sub group data in the Promising Pathway Act, see their whole web site at the Musella Foundation. As he says in a short video, focused especially for brain cancer patients:
"While these therapies might not meet the criteria for FDA approval, they hold potential, especially in combinations, and we need EASY access to them, NOW!" "This is where the Promising Pathway Act comes in to play. It aims to rectify the limitations of Right-to-Try, Expanded-Access and Accelerated-Program. The act proposes a conditional approval pathway for FDA endorsement and establishes a robust learning system. Under this system, every patient using these drugs approved under this pathway, will be meticulously tracked in a regulatory-grade registry. This real time data will empower doctors to decide which treatments and combinations are worth pursuing".
LTSL-Dox + Hyperthermia is such a case in combination where subsets of patients clearly benefited but not meeting the overall FDA endpoints means the treatment is not available to such subsets who could benefit in a range of cancers. In fact, as suggested by Dr. Musella on a recent call, since we are using LITT as a laser probe, there could be additional combinations including photodynamic therapies that could be included. It just needs testing, properly.
DNKO, and our close knit group of dedicated and talented collaborators and clinicians, will now bring these technologies and treatments through to see if they can benefit brain cancer patients and their families.