Targeted Chemotherapy

We are employing the Cell-in-a-Box® technology as a platform to develop therapies for solid cancerous tumors using targeted chemotherapy. Using pancreatic cancer as an example, with Cell-in-a-Box®, genetically engineered live human cells that produce an enzyme designed to convert the cancer prodrug ifosfamide into its cancer-killing form are encapsulated. The capsules containing these cells are implanted in a patient in the blood supply near the tumor. The cancer prodrug ifosfamide is then given intravenously at one-third the normal dose.

Thus, the ifosfamide will be converted into its “cancer-killing” form at the site of the tumor instead of in the liver where it is normally converted. We believe placement of the Cell-in-a-Box® capsules near the tumor enables the production of optimal concentrations of the cancer-killing form of ifosfamide at the site of the tumor. The presence of the capsules in the blood vessel leading to the tumor did not prevent the blood flow to the tumor.

The cancer-killing metabolite of ifosfamide has a short half-life, which we believe will result in little to no collateral damage to other organs in the body. In an earlier Phase 1/2 clinical trial which used our pancreatic cancer treatment in very sick patients with advanced pancreatic cancer, this targeted chemotherapy not only reduced the tumor size but also resulted in no obvious adverse side effects attributable to the therapy.

PharmaCyte’s pancreatic cancer treatment has received the Orphan Drug designation from drug regulatory authorities in the U.S. and the E.U. This designation carries with it 7 years of marketing exclusivity in the U.S. and 10 years in the E.U., after the product has been approved for marketing by these authorities

Pancreatic Cancer

Pancreatic cancer is a very aggressive cancer with a poor prognosis. It is the third leading cause of cancer-related deaths in the U.S. and the seventh leading cause of cancer-related deaths globally. The five-year survival rate is 8%, reportedly the lowest survival rate of any cancer. It is expected that in 2016 there will be approximately 53,000 new cases diagnosed in the U.S. In Europe, the estimate is approximately 90,000. Unfortunately, about 71% of patients will die within the first year of diagnosis. More than 90% will die within two years of diagnosis. Without treatment after diagnosis, patients have a three and one-half month median life expectancy.

There is no cure for pancreatic cancer unless the tumor is surgically removed in its earliest stages of growth. Patients with pancreatic cancer are not normally diagnosed until the cancer is advanced and inoperable. Since the first drug (gemcitabine) was approved in the U.S. for pancreatic cancer in 1996, approximately 40 registrational clinical trials have been conducted. In spite of this, little improvement in median survival time and percentage of one-year survivors has occurred. Most success was achieved when gemcitabine was given in combination with another chemotherapy drug.

The current standard of care for advanced pancreatic cancer is the combination of Abraxane® (a nanoparticle albumin formulation of the drug paclitaxel (Taxol®) plus gemcitabine. This combination was approved by the U.S. FDA in September 2013. This combination increased the median survival time by 1.8 months, as compared to gemcitabine alone. It increased the one-year survival time from 22% with gemcitabine alone to 38% with Abraxane® plus gemcitabine. There are severe side effects associated with this combination chemotherapy.

PharmaCyte’s Pancreatic Cancer Therapy

We are developing a therapy for pancreatic cancer to address a critical unmet medical need. This need exists for patients with pancreatic cancer whose tumors are locally advanced, non-metastatic and inoperable but where maximum antitumor response to Abraxane® plus gemcitabine has been achieved.

Although several therapies have been tried in this situation, until recently, the most commonly used treatment is chemoradiation (CRT); i.e. the combination of the cancer drug capecitabine plus radiation. However, the results of a Phase 3 clinical trial, recently reported in the Journal of the American Medical Association, addressed whether CRT is more effective than chemotherapy alone. In patients with locally advanced, inoperable pancreatic cancer whose tumors no longer responded to gemcitabine or gemcitabine plus erlotinib (standard initial therapies at the time the clinical trial was conducted) patients were treated with the same chemotherapy or with CRT. In both cases CRT was not meaningfully more effective than chemotherapy alone and both gemcitabine alone and gemcitabine plus erlotinib were equally effective vs. CRT. Consequently, these patients have no known effective treatment alternative once they have completed initial chemotherapy.

Subject to FDA approval, we plan to commence a clinical trial in 2017. The trial is designed to show that our Cell-in-a-Box® plus low-dose ifosfamide therapy can serve as an effective and safe consolidation chemotherapy for patients whose tumors no longer respond after four to six months of therapy with Abraxane® plus gemcitabine. The trial will take place in the U.S. with study sites in Europe. Translational Drug Development (“TD2”) will conduct the trial in the U.S. Clinical Network Services (“CNS”) will conduct the trial in Europe in alliance with TD2. TD2 will be responsible for clinical development plans, program analysis, medical writing, clinical management and database development.

The trial will be open-label, multi-site, two-armed and randomized. Patients will be randomized to receive our therapy or gemcitabine alone. Only patients whose tumors are locally advanced, inoperable and non-metastatic will be eligible to be enrolled. Patients must have been treated with Abraxane® plus gemcitabine for four to six months at which point maximum response to that combination will have been reached. Each patient who will receive our therapy will receive a single implantation of 300 Cell-in-a-Box® capsules plus multiple courses of low-dose ifosfamide until they receive no further benefit from this therapy.

The primary endpoints, or outcomes to be measured in the upcoming clinical trial will be progression-free survival assessed after 26 and 52 weeks, as well as safety and tolerability of the comparative therapies. The secondary endpoints include: (i) overall survival at 14, 26 and 52 weeks; (ii) objective response rate at 14, 26 and 52 weeks as measured by CT and PET scans; (iii) assessment of a patient’s tumor going from inoperable to operable after 14, 26 and 52 weeks; (iv) time to onset of pain and pain management after 14, 26 and 52 weeks; and (v) assessment of the patients’ overall quality-of-life while undergoing our therapy.

In a previous Phase 1/2 open-label, single site 14-patient clinical trial using our therapy and in which only two courses of ifosfamide were given, our treatment was shown to be safe and effective.(See Figure 3). In fact, when the results of that trial were compared to historical data for gemcitabine (the “gold standard” for pancreatic cancer at the time that this trial was conducted) the percentage of one-year survivors was double that previously reported for gemcitabine, the median survival of patients was substantially increased as compared to gemcitabine, and in contrast to gemcitabine, no treatment-related side effects were seen with our therapy. Interestingly, in 3 of the 14 patients, their advanced-stage tumors were reduced in size to the point where they would have been operable.

Breast Cancer

For 2016, the American Cancer Society has estimated that more than 246,000 cases of breast cancer will be diagnosed in the U.S. alone and more than 40,000 individuals are predicted to die from this disease, with about 99% of these being women. Worldwide, breast cancer is the fifth most common cause of cancer deaths and is second only to lung cancer in overall prevalence. More than one million new cases of breast cancer are diagnosed each year.

PharmaCyte Breast Cancer Treatment

According to the American Cancer Society, ten different chemotherapeutic drug combinations have been widely used for years to treat various forms of breast cancer. Nine of these ten combination chemotherapies use the anticancer drug cyclophosphamide (Cytoxan®) as one of the components of the combination.

Cyclophosphamide is a “sister” drug to ifosfamide – the anticancer agent used in the clinical trials in patients with advanced, inoperable pancreatic cancer using PharmaCyte Biotech’s treatment for pancreatic cancer. Both drugs are classified as “prodrugs” and must be activated (converted to their cancer-killing form) for them to be effective. The cytochrome P450 enzyme system in the liver activates both cyclophosphamide and ifosfamide.

For PharmaCyte’s pancreatic cancer treatment, the cells that are encapsulated using the Cell-in-a-Box® technology
contain an isoform (known as CYP2B1) of the cytochrome P450 enzyme system and are efficient at activating ifosfamide. Because of the similarities between ifosfamide and cyclophosphamide, the same encapsulated cells as those used in the pancreatic cancer clinical trials should efficiently and effectively activate cyclophosphamide into its cancer killing form in developing a novel treatment for breast cancer.

Veterinary Phase 1/2 Trial in Dogs with Breast Cancer

To test this hypothesis, Cell-in-a-Box® capsules containing cells with high CYP2B1 activity were used in combination with cyclophosphamide in a veterinary Phase 1/2 veterinary clinical trial in dogs with spontaneously-occurring mammary tumors. This is a good animal model system for testing the effectiveness of cyclophosphamide in treating breast cancer in humans because the development and pathological features of mammary tumors in dogs are very similar to those seen in breast cancer in women. Spontaneous mammary tumors account for about 70% of all cancers in dogs. Usually such tumors are removed surgically, but it has been estimated that more than 55% of dogs develop new cancers after such surgery. Cyclophosphamide was chosen for this veterinary Phase 1/2 trial rather than ifosfamide because it is often used to treat breast cancer in women as well as mammary tumors in dogs. In addition, as noted above, it is a component of most combination chemotherapy regimens used against breast cancer in humans.

A total of 16 dogs were enrolled in the preclinical trial. The dogs were divided into two groups. One group of 6 dogs was treated intravenously with cyclophosphamide alone at a dose of 7 mg/kg of body weight, in four treatments on days 2, 9, 22, and 29. In the 10 other dogs, 20 Cell-in-a-Box® capsules containing the cyclophosphamide-activating cells were implanted at 5 sites around their tumors on day 0 (two days before administration of the first dose of cyclophosphamide) and then cyclophosphamide was administered in the same regimen as the other 6 dogs. Three of the 10 dogs treated with the encapsulated cells/cyclophosphamide combination had two tumors as did one dog treated with cyclophosphamide alone.

As in the pancreatic cancer clinical trials in humans, the capsules and the cells within them were well tolerated – no “safety” issues were seen in the dogs that could be related to the presence of the capsules or to their implantation over the entire 56-day observation period. Although mild side effects from the use of cyclophosphamide were observed in both groups of dogs, these were no more severe than those seen when this drug is used alone to treat mammary cancer in canines.

The final evaluation of the effect of the treatments on tumor size were graded as follows: Complete remission (CR), Partial remission (PR) – regression of the tumor by at least 50% of the initial tumor mass, Stable disease (SD) – regression of the initial tumor mass by less than 50% or its enlargement by less than 25%, Progression of disease (PD) – increase in initial tumor mass of at least 25% or the occurrence of new tumors. Six of the 11 tumors treated with the encapsulated cells/cyclophosphamide combination showed a PR while the other 5 showed SD. Of the 7 tumors in the 6 dogs that received cyclophosphamide alone, 6 tumors showed SD and the other exhibited PD. The median tumor size reduction of the tumors in dogs treated with the combination was 53%. This is in contrast with only a 21% reduction of the size of the tumors in the dogs treated with cyclophosphamide alone.

For one of the dogs with two tumors in the combination-treated group, both tumors showed a similar reduction in size (65% and 62%). In a second dog with two tumors in this group, one tumor that received the combination treatment was reduced in size by 70% while the other tumor, which was exposed to cyclophosphamide alone, was reduced in size by only 14%. The tumors in dogs that were administered cyclophosphamide alone were reduced in size by only about 19%.

The results of this study indicate that the combination of the Cell-in-a-Box® cellulose-based live-cell encapsulation and cyclophosphamide may prove to be of significant benefit not only for the treatment of mammary cancers in the veterinary setting, but also may ultimately find a role in the treatment of breast cancer in humans by optimizing the cancer-killing activity of cyclophosphamide when that drug is used for breast cancer

Malignant Ascites

We are also developing a therapy to delay the production and accumulation of malignant ascites fluid that results from abdominal tumors. Malignant ascites fluid is secreted by such tumors into the abdomen after the tumor reaches a certain stage of growth. This fluid contains cancer cells that can seed and form new tumors throughout the abdomen. Malignant ascites fluid accumulates in the abdominal cavity, causing swelling of the abdomen, severe breathing difficulties and extreme pain.

Malignant ascites fluid must be surgically removed on a periodic basis. This is painful and costly. There is no available therapy that prevents or delays the production and accumulation of malignant ascites fluid. We have been involved in a series of preclinical studies at TD2 to determine if our pancreatic cancer therapy can delay the production and accumulation of malignant ascites fluid from abdominal cancers. If successful, we plan to conduct a clinical trial in the U.S. with additional study sites in Europe. As for the pancreatic cancer study, TD2 will conduct this trial in the U.S. and CNS will conduct it in Europe in alliance with TD2.