Dr Low spoke with IO Learning about OTL38, a tumor-targeted dye developed in his laboratory at the Purdue University Institute for Drug Discovery. Dr Low discusses the merits of fluorescence-guided cancer surgery, as well as possible future uses for OTL38 in the field of interventional oncology.
Please briefly describe intraoperative molecular imaging with OTL38.
When a patient is brought into the hospital with a suspected malignant lesion, they are usually evaluated by a computed tomography (CT) scan or with magnetic resonance imaging (MRI). These imaging modalities allow the doctor to see an abnormal density or abnormal-looking structure in the body, but they often can’t distinguish whether the abnormality is cancer or not. Moreover, the imaged lesion may be buried deep in a particular organ, like a liver or a lung, and its exact location may be difficult to find during the surgical procedure.
If the initial scan looks suspicious, a surgeon will often decide to operate to remove the lesion. When the surgeon begins the operation and opens up the patient, he or she can often identify the cancer tissue by either visual inspection or by palpation. However, cancer tissue often looks very similar to normal tissue, if not identical, and is often buried, so the malignant tissue is frequently difficult to detect by palpation. To remedy these deficiencies, we have developed a tumor-targeted fluorescent dye (OTL38) that is injected intravenously just before surgery. The dye circulates throughout the body, but is only retained in malignant cells and clears from normal cells. Within an hour or so, the malignant cells are brightly fluorescent and the normal cells are dark. When the surgeon turns on a fluorescent light, the tumor with the entrapped fluorescent dye glows brightly, like the moon against a dark sky.
What are the main benefits to using OTL38?
OTL38 allows the surgeon to visualize and resect otherwise undetectable malignant lesions. The dye also enables the surgeon to examine the tumor bed that contained the resected malignant nodule to see if there’s any residual fluorescence, ensuring that complete tumor removal can be achieved. Moreover, if the cancer nodule is buried very deep within an organ — for example, in a lung, liver, or breast — the surgeon often won’t know exactly where to cut to find the lesion. In these cases, OTL38 can essentially provide a fluorescent beacon to illuminate the pathway to the cancer nodule, which results in less damage to healthy tissue during resection.
Can you tell us a little bit about the phase 2 results of the studies on OTL38?
The first phase 2 study was completed on ovarian cancer patients roughly a year ago. It was a single dose, open-label, prospective study that enrolled 48 patients, with 44 patients completing the study and becoming eligible for evaluation. Each patient was injected with 1-2 mg OTL38 shortly before surgery and collectively a total of 225 lesions were evaluated. The most exciting result was that 48.3% of the patients who underwent the surgery had at least one additional malignant lesion detected exclusively by the fluorescent dye. In other words, had these patients not had the fluorescent dye, the lesion would not have been seen, the patient would have been sewn back up, and the cancer would have remained inside. That patient would have likely recurred and possibly died. Thus, based on the phase 2 data, OTL38 enabled surgeons to find additional cancer in almost half of the study patients, which is enormously good news for ovarian cancer patients.
Can you tell us about the specificity and sensitivity of the OTL38 dye?
There are a few parameters that are used to define the specificity of a fluorescent dye for cancerous cells. When our phase 2 data were adjusted for actual correlation of detection among multiple lesions within a single patient, the sensitivity was estimated at ~98%. The positive predictive value (in other words, the ability to predict whether cells are cancerous if they fluoresce) was estimated at ~95%. Therefore, the sensitivity and specificity were very high.
Are there any potential side effects from intraoperative molecular imaging?
Eight of the 48 patients had mild drug-related events, such as redness at the site of injection, nausea, or mild pain. These symptoms were no worse than patients often experience when injected with a placebo, and the FDA therefore expressed no concerns over the toxicity of the drug.
Can you tell us about the phase 2 results in lung cancer patients?
I will preface this by saying that lung cancer and ovarian cancer are two very different diseases. In ovarian cancer, the cancer spreads throughout the peritoneal cavity, and is often on the surface of organs such as the intestines and omentum, etc. Lung cancer, on the other hand, spreads very differently. At least initially, it will often spread within the lungs, but not on the surface; that is, it is frequently buried fairly deeply within the lung tissue.
The phase 2 lung cancer trial recruited 110 patients, with 92 deemed eligible for analysis. Again, 1-2 mg of the OTL38 dye were injected shortly before surgery. And again, there were no serious adverse events, and only mild reactions in a few cases during dye administration.
One or more additional cancers were found in 8% of the patients, and difficult-to-find primary lesions were localized with the aid of OTL38 in 12% of the patients. For example, a surgeon who might have seen a lesion on a CT scan but wasn’t able to find it using palpation or visual inspection during surgery was faced with a choice: should he or she start cutting and digging until he/she finds the suspicious lesion, destroying much healthy tissue in the process or should the surgeon leave the unfound lesion in the patient? This uncertainty is obviously reduced by OTL38, because the fluorescent dye renders the cancer cells much easier to find. With the availability of OTL38, the surgeon administers the dye, turns on the fluorescent lamp, sees the fluorescent area, and simply goes there directly to resect the cancer. Thus, surgeons who were unable to find suspicious lesions in 12% of the study patients were subsequently able to locate them after activating the fluorescent light. In addition to the above benefits, in another 9% of patients, surgeons were able to detect and remove additional cancer tissue in the tumor bed after they had thought that they had successfully resected all of the malignant tissue. In other words, the surgeon was certain at the time of tumor removal that he or she had cut out the entire tumor, but upon turning on the fluorescent light, he/she noted additional fluorescent tissue indicating residual diseased tissue. Finally, in 8% of the patients, the stage of the cancer was changed after visualization with OTL38, which means the method of postsurgical treatment generally changed.
What is the next step for the investigation of the OTL38 dye?
We are moving forward with phase 3 clinical trials in both ovarian and lung cancer. The FDA has given us fast track status for both clinical trials, which will al-low us to accelerate completion of the trials. They’ve conferred a special protocol agreement (SPA), which means that the FDA agrees on the requirements for regulatory approval before initiation of the trial. Thus, if the results continue to be promising, approval of the drug will occur soon after the end of the phase 3 tri-al, since we have agreed on the criteria for approval ahead of time. We have the SPA in place for both trials, which is a big achievement. With these considerations, the FDA has been extremely helpful in helping us make the dye available to patients as soon as possible.
Has the OTL38 dye been investigated in other types of cancer?
We’ve used OTL38 in limited investigator-sponsored trials on other cancers, such as kidney cancer and brain cancer. A benefit was observed in both cases, but the data were not obtained under strict clinical trial conditions, so the clinical results cannot be used to support FDA approval.
At this point, the fluorescent dye has been demonstrated to be safe for use in humans, and so it would be up to the surgeons and management at On Target Laboratories, the company that I founded to develop this drug, to decide which other cancers to investigate in the future, and then to obtain FDA approval for use of the dye in those additional cancers. It would surprise me, however, if the dye weren’t tested by physicians in several other cancers after its approval for ovarian and lung cancers.
Is there potential for these dye molecules to be utilized in interventional oncology applications in patients who aren’t surgical candidates?
I believe that there are indeed several other potential applications for OTL38. For example, let’s suppose a woman has a suspicious density in her peritoneal cavity that was imaged by CT or MRI. A good fraction of these cases, perhaps 70% or so, are benign, but it can be difficult to assure it is not cancer without a pathology examination. In the future, it may be possible to insert an optical fiber through a small hole in the belly in an outpatient procedure and take a quick look for any fluorescent tissue. If the suspicious area fluoresces, the cancer is confirmed, and the surgeon can then perform a full operation to remove it. If the area doesn’t fluoresce, the patient is rewarded with peace of mind and together they can decide whether to proceed with surgery.
Another example of a potential use for OTL38 would be to look for recurrent disease in a female patient with stage 3 or stage 4 ovarian cancer. Generally, this type of patient would undergo surgery, then heal for a few weeks, and finally undergo chemotherapy. The oncologist would then monitor a cancer marker in the bloodstream called CA-125; if the marker starts to rise, the surgeon would have to confess that “unfortunately, we didn’t get all of the diseased tissue during surgery, and your cancer has recurred.” However, by the time the elevated CA-125 is detected, it’s often too late. In this example, the patient will have already failed the first chemotherapy, and by the time the elevated CA-125 is detected again the available treatments may have a lower probability of success.
On average, if you look across all ovarian cancer patients, the increase in CA-125 that is seen in recurrent patients is first observed at ~11 months post surgery. The use of OTL38 dye with an inserted optical fiber might enable detection of the recurring cancer in these patients long before the rise in CA125; ie, enabling the oncologist to hopefully find a drug that successfully treats the cancer before it becomes too entrenched. Therefore, the ability to use OTL38 to take a second look before it’s too late could save lives.
Any final thoughts?
I look forward very much to the time when OTL38 dye becomes available to the general public, as I feel it has significant potential to reduce the morbidity and mortality associated with many cancers.
Disclosure: Dr Low reports grants, personal fees, and stock from On Target Laboratories, Inc, as well as a patent on OTL38 licensed to On Target Laboratories, Inc.
Address for Correspondence: Philip Low, MD, On Target Laboratories, 1281 Win Hentschel Blvd, West Lafayette, IN 47906. Email: firstname.lastname@example.org