Investor FAQs

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If a subject has two lesions in different segments and the investigator is planning on resecting one lesion which is over 7cm and performing the RFA on a second lesion that is in study range, would this subject be eligible? Both lesions would be done during in the same setting.: This subject would not be eligible.
Does the protocol allow treatment to increase the subject's albumin and improve their screening results?: No, this is not allowed as albumin is a part of Child Pugh's scoring system.
Is a subject with ruptured HCC eligible for the HEAT study?: No, this would fall under exclusion criterion 1 because ruptured HCC is a serious life-threatening condition requiring intensive medical management. Since the patient is in an acute condition the site should provide standard of care, it is unethical to try any investigational medication.
If a subject had a previous quadruple bypass last year, would this subject be eligible?: The PI should decide if the previous quadruple bypass is considered to be or not to be a serious medical condition which would exclude the subject from the study. The PI should ensure that none of the conditions listed in Exclusion criterion #1 have occurred within the last 6 months.
If a particular drug has multiple ingredients, should each ingredient be listed on the Concomitant Medication CRF. For example, if "Augmentin" is listed as a generic drug should the study coordinator record it as "Amoxicillin" in one row and "Clavulanate" in another with the corresponding doses?: The ingredients of a particular medication should not be split across separate lines. In this example, the site can enter "Augmentin" or the ingredients on the same line, i.e., "Amoxicillin/Clavulanic Acid".
Do potential subjects have to meet the laboratory inclusion/ exclusion criteria required for randomization (e.g. platelet count >75,000/mm3, ANC > 1500/mm3, hemoglobin >10 g/dL, etc) from both the screening (within 14 days of RFA) and within 48 hrs of RFA time points?: ThermoDox® contains doxorubicin which may cause bone marrow suppression. Therefore, Celsion is strictly enforcing the laboratory inclusion/exclusion criteria. The 48 hour labs must meet study criteria in order for patients to be involved in this study. If the 48 hr labs do not fulfill criteria, the RFA treatment date may be postponed, if feasible, otherwise the patient may not be administered study drug. Patients can be treated accordingly provided that the labs recover to acceptable range upon repeating. If the RFA treatment cannot be rescheduled, the subject should be considered randomized, but never treated on study drug.
What is the timeframe allowed for historical use of lipiodol?: The problem with lipiodol is that there is persistent enhancement of the HCC lesions for a long period ( up to 1 year) of time after the administration of lipiodol and the core imaging laboratory would not be able to properly evaluate the subject. If the Most recent CT does not have any evidence of residual tumor enhancement then it is possible that the subject would be able to be enrolled, however this would have to be determined by a site Radiologist and PI.
If an ECG for a potential subject reads "normal sinus rhythm, Inferior infarct, age undetermined" Is this exclusionary?: If the PI considers that the MI happened over 6 months ago and there is no CHF to exclude this patient it's ok to enroll. You might need to look at the previous EKGs, if available, to determine age of MI.
What is the time frame for being disease-free if a patient has had prior cancer surgery (for another primary cancer)?: In order to enroll such a patient 1) the site must confirm that the liver lesion is HCC and not a metastasis from the prior cancer by biopsy, 2) patient must be disease-free (not concurrent) for at least six months since prior cancer a serious medical illness, and 3) the patient cannot have previously received doxorubicin to treat his other cancer.
What is the action to be taken by site if subject continues to have high bilirubin result (2 to 3 mg/dl) on Day 7 post-RFA?: If total bilirubin is stable at 2 to 3 mg/dL on Day 7, no specific action is required. If on Day 7, bilirubin level is above 3 mg/dL then these patients should be followed carefully until bilirubin level is below 3 mg/dL. Day 14 assessment should be performed for all patients per protocol.
If a subject is on a transplant list, but is not scheduled for a transplant yet, is there a timeframe when this patient is eligible for enrollment in the HEAT Study?: If the subject was expected to be transplanted within the next six months, then this would be considered immediate, and such a subject should not be enrolled in the HEAT Study. Or, as long as a subject was not expected to be transplanted within the next six months (and fits all other eligibility criteria), we would consider the subject eligible.
Some of the eligibility criteria occurs close to treatment day, therefore, is it ok to have the final copy of the eligibility form signed the same day as treatment, or must this be done prior to randomization?: On page 13, the date under the Investigator's Statement is not the date of his signature, it is the date that the PI decided the patient was eligible and could be randomized. So this date should be on or before the randomization date.
If a patient has a documented history of mild ascites which was treated with diuretics and has resolved, would this prior documented ascites exclude him/her?: If the ascites were reversed and controlled by medication, the site may enroll this patient under the condition that he/she meets all other study criteria.
If a patient has had rare encephalopathy documented, but was treated with lactulose, and now does not appear to have encephalopathy, is he excluded: If the encephalopathy was reversed and controlled by medication, the site may enroll this patient under the condition that he/she meets all other study criteria.
Should the placebo study drug infusion be diluted with D5W or normal saline? Or is this up to the site? The instructions state D5W but the accountability form states saline.: The placebo study drug infusion is not diluted. A 250mL D5W infusion bag should be used as stated throughout the pharmacy manual and protocol. The ThermoDox study drug infusion is reconstituted with D5W only (normal saline stability data with ThermoDox is not available). The placebo pre-medications are also not diluted the appropriate amount of saline or D5W should be drawn into the infusion bag or syringe (which is up to the site).
Regarding pre-medication preparations, can the ranitidine be prepared in a NS mini-bag instead of a 1/2 NS mini-bag?: Since the pre-medications may be dosed and prepared according to institutional practice or package insert according to the pharmacy manual, ranitidine may be prepared in a NS mini-bag instead of a 1/2 NS mini-bag.
What is the definition of start and end times of RFA which are recorded on CRF (page 22)?: The start time of the RFA is the start time of heating. The end time is the time to last roll off.
Some procedures are required to be carried out immediately Post RFA (such as ECG, blood taking). Are these procedures performed while the patient is still in the recovery room or when he/she is moved to the ward in a stable manner?: Month 1 procedures should be completed 28 days (+/- 3 days) after the RFA date.
For the patient reported outcome questionnaire The total score is calculated by the (sum of all individual scores multiplied by 8) divided by the number of items answered. If the total score that is calculated per these guidelines is a decimal number, how should this value be recorded on the CRF?: Normal rounding rules apply. So if the number is greater than or equal to .5, the total score should be rounded up to the next number (i.e., 6.7 would be recorded as 7). If the number is less than .5, the total score should be rounded down (i.e. 6.3 would be rounded to 6).
The protocol states that IV pre-meds should be administered 45 minutes before RFA, and IV ThermoDox or placebo be administered 30 minutes later, 15 minutes prior to RFA (see pages 28 and 29 in the protocol). How important is the 30 minute timeframe between IV pre-meds and ThermoDox?: It is important that the IV pre-meds be administered as close as possible to 30 minutes prior to ThermoDox administration.
It is stated that hydration with normal saline can be done for the patient with diabetes mellitus or higher Creatinine clearance to reduce the risk of CIN (Contrast Induced Nepheopathy). For prophylaxis purposes, is it ok to do this procedure for the rest of the patients whose Creatinine clearance is not high?: It is okay to administer normal saline as prophylaxis in non-diabetic patients or even when Creatinine clearance is normal if the investigator considers that prophylaxis is required for patient safety.
Can the site use the infusion pump to infuse the ThermoDox? In the protocol, it is recommended to use the free flowing IV line.: The priority is to protect the blinding and ensure that the study medication is infused in 30 minutes. Unless there is a specific reason, it is suggested to use a free-flowing line. If the site's infusion pump is only a simple device through which the IV tubing flows to control drip-rate then it is okay to use. With the use of the infusion pump, if the tubing goes through the pump and it is not covered by the black blinding sleeve, it would be difficult to maintain the blind. Although infusion pumps are okay to use, syringe pumps cannot be used because blinding cannot be maintained.
Please clarify the criteria of hepatic vein tumor invasion/thrombosis (exclusion criteria #9). For example, if the lesion is close to or almost meets the vein but no thrombosis is present, is this considered invasion or not?: The purpose of excluding hepatic vein invasion/thrombosis is consistent with standard RFA practice. If applied near a large vessel (inferior vena cava), the vessel acts as a heat sink to the radio-frequency energy and can hinder adequate temperatures and prevent tumor necrosis. This will affect efficacy even when there is no thrombosis. If the lesion touches a major blood vessel then the lesion cannot be safely ablated. Hence, these patients should be excluded.
Is platelet transfusion during the RFA procedure acceptable if the subject has possibility of bleeding?: According to Section 11, the investigator can use supportive therapy including blood products at their discretion. Platelet transfusion as a precautionary measure is acceptable.
Protocol (section 10.1.4) makes a specific reference to oral body temperature. In many sites, the usual practice is to measure tympanic temperature. Is a tympanic temperature allowed?: The sites should (1) attempt to use oral temperature (2) if the sites or patient declines oral measurement then tympanic temperature is acceptable and is recorded on the case report form with a note indicating the use of tympanic vs. oral reading.
For the ablation procedure, there is a place on the case report form (page 23.1) to record temperature, impedance and power values. Since the values can vary throughout the whole procedure. Should we record highest impedance during the cycle?: Recordings depend on the generator used:

For Valley Lab, the beginning impedance and the 15 to 30 second post ablation temperature must be recorded. Power recorded should be 250W (max capacity) for the current model.

For Boston Scientific, the Start and Stop time is key for this instrument which would indicate Roll-Off where rise in impedance with corresponding drop in power is achieved (min of 5 minutes). Therefore, temperature and impedance is not required. Power recorded should be 200W for current model.

For Angiodynamics (RITA), the 15 to 30 second post-ablation temperature must be recorded. Must be > 60 in two or more tines, therefore record the second highest temperature in the tines of an array. Power recorded should be 200W for current model. The impedance value is not necessary.
What is the difference between ThermoDox and DOXIL?: DOXIL places doxorubicin into a fat bubble called a liposome and another layer of methoxypolythylene glycol to allow DOXIL to evade detection and destruction by the immune system, which increases the time the drug is in the body, it is not thermo-sensitive. On the other hand, ThermoDox is a thermally activated when temperature is above 40 degrees.
A subject may be switched to another treatment depending on the pattern of recurrence. If so, do they need to be discontinued from study?: Yes, the subjects must be discontinued from study since they will no longer meet eligibility criteria; however, they will continue to be followed for overall survival. If they remain on RFA, the patients will have the option to be retreated for a total of 6 treatments.
If an ablation cannot be completed for a single large lesion (tumor size > 4cm) or all the tumors at one time, due to the patient pain tolerance of multiple RFA punches, is the patient eligible for retreatment?: Yes, according to the protocol, patients can be retreated 21 days post ablation, but no later than 14 days after the first post-ablation CT scan assessment.
Protocol section 10.1.4 makes a specific reference to oral body temperature. In many sites, the usual practice is to measure tympanic temperature. Is a tympanic temperature allowed?: The sites should (1) attempt to use oral temperature (2) if sites/patient refuses oral measurement then tympanic temperature is acceptable. The tympanic temperature is recorded as it is on the CRF, and a comment should be inserted about not using oral recording.
A subject may be switched to another treatment depending on the pattern of recurrence. If so, do they need to be discontinued from study?: Yes, the subjects must be discontinued from study since they will no longer meet eligibility criteria; however, they will continue to be followed for overall survival. If they remain on RFA, the patients will have the option to be retreated for a total of 6 treatments.
If an ablation cannot be completed for single large lesion (tumor size > 4cm) or all the tumors at one time, due to the patient not being able to bear the pain of the number of RFA punches, is the patient eligible for retreatment?: Yes, according to the protocol, patient can be retreated 21 days post ablation, but no later than 14 days after the first post-ablation CT scan assessment.
Will Celsion reimburse patients for transportation costs if they live a great distance from the site?: Celsion is willing to cover the patient's transportation expenses, but this would need to be discussed on a case by case basis.
Can IV propofol be used as a sedative during induction of anesthesia?: Since Propofol is a lipid soluble sedative it may combine with the liposome of ThermoDox and lead to drug availability problems. Since we do not have any data on this drug-drug interaction, we suggest that this be replaced with another non lipid soluble agent.
Are subjects with trace ascites eligible for this protocol?: If the ascites cannot be controlled medically (e.g. diuretics) the risk for bleeding is too great. If the patient had ascites in the past but it was reversed and is controlled by medications they can enroll the patient if other study inclusion/exclusion criteria are met.
Is it possible to enroll in the study patients who were previously radically ablated?: No, any previous treatment of HCC is not allowed as per exclusion criteria #3.
Is lipiodol allowed in this study?: No, lipiodol use is discouraged. Lipiodol is commonly used in arteriograms to enhance images in order to confirm diagnosis. It is difficult to assess necrosis with use of lipiodol, interpretation is difficult due to staining of the tumor. If lipiodol was recently used for diagnosis, it is best not to include the patients for this study. However, it is acceptable if lipiodol was used historically (eg more than 1 year ago) for diagnosis of other conditions.