Patented DocePLUS™

OVERVIEW

PLUS THERAPEUTICS is developing DocePLUS™, a patented albumin-stabilized PEGylated liposomal formulation of docetaxel.

Docetaxel Background

Docetaxel is a modification of an extract from the European yew tree and exhibits anti-tumor activity by binding to and hyper-stabilizing microtubules, thereby preventing de-polymerization necessary for cell division.  Docetaxel for injection was originally approved under the TAXOTERE® brand name by the European Commission in 1995 and by the U.S. FDA in 1999.  Sanofi reached peak TAXOTERE® global sales of approximately $2.7 billion in 2010.  TAXOTERE® and docetaxel generics, approved in the U.S. starting in 2011, continue to be administered as workhorse chemotherapeutics today and are indicated for the treatment of a number of cancers including breast cancer, head and neck cancer, stomach cancer, prostate cancer and non-small cell lung cancer.  However, docetaxel use is associated with several shortcomings including, but not limited to:

  1. Poor water solubility requires use of solvents, such as Tween 80, for intravenous (IV) administrations; solvents can potentially contribute to treatment-related adverse events such as hypersensitivity reactions, nausea, fatigue, and anemia
  2. Current formulations often complicate drug delivery and can alter both the pharmacokinetic and toxicity profiles
  3. Requires pretreatment medications such as dexamethasone
  4. Well known to cause dose-dependent and sometimes disabling peripheral neuropathy
  5. Quickly metabolized

References:

TAXOTERE is a registered trademark of Sanofi.

Docetaxel Molecule

DISEASE TARGET – SMALL CELL LUNG CANCER

While there are a multitude of potential disease targets for DocePLUS™, PLUS THERAPEUTICS intends to initially focus on small cell lung cancer (SCLC), an area in which there has been few advances in therapeutic options for patients over the last 30 years.

Epidemiology

In 2018, lung cancer was estimated to have accounted for 13.5% of all new cases of cancers worldwide (234,030) and is the 2nd most common cancer, following only prostate cancer and breast cancer in men and women, respectively.  These incidence rates hold true across all ethnic groups with the exception of Hispanics, in whom colorectal cancer occurs more frequently than lung cancer.  Incidence rates of lung cancer for both men and women, in all racial and ethnic groups, decreased over a 5-year period (2010–2014), except for American Indian/Alaska Native men and Asian/Pacific Islander women, in whom rates remained stable.

According to the National Cancer Institute, lung cancer continues to be the leading cause of cancer-related death among Americans with an estimated 154,050 deaths (25.3% of all cancer-related deaths) in 2018 alone. Approximately 13–15% of bronchogenic carcinomas are classified as Small Cell Lung Cancer (SCLC) and 5.8 per 100,000 new cases of SCLC are diagnosed each year in the United States.

SCLC is an aggressive neuroendocrine malignancy characterized by high metastatic potential and poor relative outcomes. Due to its propensity to metastasize widely and early in the disease course, SCLC is considered the most lethal lung cancer subtype, with 5-year relative survival rates ranging from 8 to 31% (depending on stage of disease).

SCLC can be classified as limited stage or extensive stage. Limited stage SCLC (LS-SCLC) is defined as disease that is limited to the ipsilateral hemithorax, regional mediastinal lymph nodes, and ipsilateral supraclavicular lymph nodes. Approximately two-thirds of patients with SCLC present with extensive stage (ES-SCLC) disease, which is characterized by distant metastasis, malignant pericardial or pleural effusions, and/or contralateral supraclavicular and contralateral hilar lymph node involvement.

Causes and Diagnosis

Smoking tobacco products, primarily cigarettes, is the most critical risk factor for the development of SCLC.  Indeed, it is rare for someone who has never smoked to be diagnosed with SCLC.  Diagnosis of SCLC is initially based on the evaluation of symptoms (eg, cough, hemoptysis, dyspnea and chest pain), which typically indicate advanced disease and can signal a poor prognosis. In addition, further confirmation of diagnosis is necessary via chest imaging with contrast-enhanced computed tomography (CT) scan and performing a tissue biopsy for staging.

Treatments

The standard of care for LS- or ES-SCLC is based on recommendations from the American College of Chest Physicians (ACCP): 4 to 6 cycles of platinum-based chemotherapy with either cisplatin or carboplatin plus either etoposide or irinotecan. Most patients with either LS or ES disease relapse or develop recurrent disease following first-line treatment. These patients are divided into two categories: refractory/resistant disease (primary progression or recurrence within 3 months of initial therapy) or relapsed/sensitive disease (recurrence > 3 months after initial therapy). In patients who relapse > 6 months from completion of initial therapy, reinitiating the previously administered first-line therapy is recommended.

Single-agent chemotherapy with HYCAMTIN® (IV topotecan) is approved and a recommended option for platinum-sensitive patients who relapse at least 60 days after initiation of first-line therapy. However, while IV topotecan demonstrates activity in this population, overall response rate (24%), response duration (3.3 months), time to progression (3.1 months), and overall survival (5.8 months) were not statistically improved over CAV (cyclophosphamide, doxorubicin, and vincristine) treatment in a randomized comparative trial. Patients receive 1.5 mg/m2 IV infusion over 30 minutes daily for 5 consecutive days, starting on Day 1 of a 21-day cycle. Thus, more effective and convenient treatment options are needed for patients with relapsed platinum-sensitive disease.

The dose-limiting toxicity for HYCAMTIN® for both SCLC and ovarian cancer is neutropenia.  In one analysis of trials comprising a total of 879 patients (4,124 courses of topotecan), Grade 4 neutropenia was reported in 78% patients and associated with 39% of the courses administered.  In this respect, it is similar to that for docetaxel, even though these 2 drugs act through very different mechanisms.  Liposomal formulations of other chemotherapy drugs have been shown to exhibit reduced side effects compared to conventional formulations, hence it is possible that DocePLUS™ will exhibit lower toxicity than either docetaxel or topotecan.  Though there are no head-to-head studies comparing DocePLUS™ with topotecan, the Phase 1 trial of DocePLUS™ reported an incidence of 30% Grade 4 neutropenia.  This compares favorably with data in the package insert of HYCAMTIN®, an FDA-approved conventional formulation of topotecan, which reported Grade 4 neutropenia frequency of 48% to 80%.  This potential difference will need to be tested in robust clinical trials.

References:

HYCAMTIN is a registered trademark of Novartis.

DEVELOPMENT RATIONALE

Docetaxel’s very poor solubility in water makes it a difficult drug to deliver into the blood. Current formulations of docetaxel overcome this problem by mixing it with a chemical called Tween 80, which acts like a detergent to improve the solubility.  However, acute reactions to the docetaxel/Tween 80 mixture — hypersensitivity reactions, nonallergic anaphylaxis, and rash — are very common. For this reason, it is recommended that patients to be treated with docetaxel be pre-medicated for 3 days with corticosteroids such as dexamethasone to reduce the risk and severity of these reactions.  PLUS THERAPEUTICS has developed DocePLUS™ to eliminate the need for Tween 80 by encapsulating docetaxel in an albumin-stabilized liposome.

Encapsulation of the docetaxel in a liposome has another important advantage. Like many chemotherapy agents, docetaxel has substantial side effects. The main toxicities for docetaxel are:
+ reduction in the number of infection-fighting cells (neutropenia)
+ nerve damage (peripheral neuropathy), and
+ hypersensitivity (allergic) reactions

These side effects can be dose-limiting, meaning that an medical oncologist will sometimes have to reduce the dose of docetaxel that they would prefer to give to the patient in order to avoid serious side effects.  In severe cases, the oncologist will sometimes need to completely discontinue the chemotherapy because of the toxicity. These toxicities happen when docetaxel pass out of the blood and enter normal healthy tissues. However, blood vessels in tumors contain gaps or windows that are not present in the blood vessels of normal blood vessels. This means that it is much easier for fluids and nanoparticles with the right size (such as liposomes) to pass out of the blood and into tumor tissue than it is for them to pass into healthy tissues. This process (referred to as Enhanced Permeability and Retention; EPR) means that liposomally-encapsulated docetaxel will selectively accumulate in tumors rather than in healthy tissues. As a result, by delivering docetaxel in a liposome, the drug (and its toxic effects) will be preferentially delivered to the tumor rather than healthy tissues. While this potential will need to be demonstrated in robust clinical trials, data from the Phase I trial of DocePLUS™ showed a 30% incidence of Grade 4 neutropenia. Though there are differences in patient populations and other factors, this compares favorably with data in the package insert of TAXOTERE®, an FDA-approved conventional formulation of docetaxel which reported neutropenia frequency as high as 90%.

In our nonclinical studies utilizing mouse tumor xenograft models (lung, prostate, pancreatic, and mesothelioma), DocePLUS™ retained the anti-tumor activity of docetaxel and was well-tolerated.  In addition, our Phase 1 study conducted under IND demonstrated that DocePLUS™ has an acceptable tolerability profile in patients with solid tumors.  In this study, DocePLUS™ could be administered safely to patients without dexamethasone premedication that is used to reduce the formulation-related hypersensitivity reactions following TAXOTERE® administration. Thus, DocePLUS™ appears to offer a therapeutic advantage compared to TAXOTERE® in terms of safety.

The proposed dosing regimen for PLUS THERAPEUTICS’ DocePLUS™ will be a 60 minute infusion on a single day, starting on Day 1 of a 21-day cycle.  This approach will reduce the patient’s number of visits to an infusion center from 5 (HYCAMTIN®) to 1 in a given 21-day cycle.

Overall, DocePLUS™ is expected to provide an effective, safe, and convenient therapeutic option for SCLC patients, thereby improving the quality of life for this population.

PUBLISHED PHASE 1 CLINICAL TRIAL RESULTS

A first-in-human, open-label, dose-escalation, Phase I clinical trial to examine the safety, pharmacokinetics, and pharmacodynamics of DocePLUS™ has been completed and published.

Study Design

Patients with advanced solid tumors (non-small cell lung, pancreas, prostate, ovary, cervix, gastric, uterine, thyroid, urachus) at 2 U.S. sites — the University of Texas Health Science Center in San Antonio and Mary Crowley Cancer Research Center in Dallas — received DocePLUS™ doses ranging from 15 to 110 mg/m2 via a 60 minute IV infusion every 21 days.  Standard pretreatment medications for docetaxel (corticosteroids, H1 and H2 antagonists, antiemetics) were not administered before the initial dose of DocePLUS™. If a patient experienced clinically significant hypersensitivty reaction after the initial dose, pretreatment medication was allowed as medically indicated before subsequent doses.  The up-front prophylactic use of granulate-colony stimulating factor (G-CSF) during the first cycle was not permitted.

The study initially followed an accelerated titration design to minimize the number of patients treated with potentially sub-therapeutic doses. At each dose level during this phase, single-patient cohorts were treated, with 100% dose escalation. The accelerated titration phase reverted to traditional 3 + 3 design, when a patient experienced a ≥ grade 2 drug-related or dose-limiting toxicity (DLT). During this phase, at least 3 patients were treated at each dose level, and dose escalations proceeded in accordance with a modified Fibonacci schema. If 1 patient experienced a DLT, up to 3 additional patients were treated at that dose level. The MTD was the highest dose at which no more than 1 of 6 patients experienced a DLT. If 2 or more patients experienced a DLT, a total of 6 patients were treated at the previous dose level. Once the MTD was determined, additional patients were treated at that dose to further confirm the safety profile of DocePLUS™. Patients who experienced a DLT stopped study medication but could restart at a lower dose level if they recovered to grade ≤ 2 AE within 1 week (up to one dose reduction allowed). Dose reduction was also made for patients who had a delay in treatment greater than 1 week due to a lack of recovery of any toxicity. Subsequent retreatment of such patients after recovery was up to the medical monitor, considering the potential benefit and risk. No intrapatient dose escalation was allowed.

Patient Eligibility

  • Included: males or females with a histologically confirmed metastatic solid tumor for whom no standard curative/palliative treatment existed or for whom treatment was no longer effective; patients receiving prior chemotherapy, radiation therapy, or biological therapy.
  • Excluded: patients with progressive brain metastases, seizure disorder, unstable angina or cardiac arrhythmia, severe chronic COPD, any active infection, and previous history of hepatitis B, hepatitis C, or HIV; pregnant women;  history of allergic reactions to docetaxel.

Response Evaluation

Patients underwent response assessment as defined in the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (version 1.1) following completion of 2, 21-day cycles of therapy. Confirmatory Positron Emission Tomography (PET) scans were obtained no more than 4 weeks following the initial documentation of an objective response. Patients with stable disease or objective response who were tolerating study drugs were eligible for continued therapy with repeat response assessments performed after every other cycle.

Patient Demographics

29 total patients received at least 1 dose of DocePLUS™ and were included in the safety analysis, including 10 patients treated at MTD (90 mg/m2). The dose levels and the number of patients treated are described below.

Dose Levels (mg/m2)Number of Patients Treated
152
301
602
758
9010
1109

Lung, pancreas, and ovarian cancer were the most common. The patient population was heavily pretreated — median of 3 prior anticancer therapies — including 9 patients who had prior exposure to TAXOTERE®.

Safety, Maximally Tolerated Dose (MTD), and Dose-Limiting Toxicities (DLT)

In general, DocePLUS™ was well tolerated and had an acceptable toxicity profile. Dose-Limiting Toxicities (DLTs) were observed in 2 of 6 patients treated at 110 mg/m2. The DocePLUS™ dose was reduced to 90 mg/m2, and the dosing cohort was expanded to include a total of 10 subjects. Although 3 patients developed grade 4 neutropenia, all patients recovered quickly without any clinically significant infectious complications. Secondary prophylaxis with granulocyte-colony stimulating factor (G-CSF) was given only to those patients who experienced a neutropenic complication from a prior cycle of chemotherapy in line with ASCO guidelines. At an intermediate dose level of 75 mg/m2, no DLTs were observed during the 1st cycle. With the 2 DLTs observed at 110 mg/m2 and no DLT in the intermediate cohort of 8 patients, the MTD for DocePLUS™ was defined at 90 mg/m2.

Across all dose cohorts and treatment courses, fatigue (reversible) was the most commonly reported treatment-related AE (79%), followed by nausea and neutropenia (both 65%), anemia (62%), anorexia, and diarrhea (both 48%). These AEs were typically mild to moderate, not clinically significant. In total, ten patients experienced a grade 2 or less hypersensitivity reaction during the 1st cycle. Prior to subsequent cycles, these patients received premedication with a combination of oral corticosteroids, histamine-1 and 2 antagonists about 12 h as well as 30 min before a test dose (1 mg DocePLUS™ over 3–5 min). This test dose was followed by administration of remainder of the protocol specified dose of DocePLUS™ over 90 min. Only one patient discontinued treatment permanently in the setting of grade 3 immediate hypersensitivity reaction during the 1st cycle (at 75 mg/m2). The remaining 18 patients were able to receive treatment without a premedication. The incidence of peripheral sensory neuropathy was 34%. Of note, no grade ≥3 peripheral neuropathy was observed in any of the treatment cohorts. No cardiac events were reported throughout the treatment period. The most common reason for study discontinuation was disease progression. No cumulative toxicity was seen in the patients receiving multiple cycles.

Pharmacokinetics

Both DocePLUS™ (encapsulated docetaxel) and free docetaxel were produced in vivo from the nanoparticle-associated liposomal preparation. DocePLUS™ demonstrated linear and dose proportional PKs. The PK exposure of encapsulated, non-encapsulated, and total docetaxel was dose proportional. The value 1.00 was within the 90 % CI range for each Cmax and AUC. The encapsulated docetaxel, non-encapsulated docetaxel, and total docetaxel versus DocePLUS™ dose suggested that both parameters were dose proportional. The encapsulated docetaxel exposure (Cmax and AUC) was ~2–3× higher than that of corresponding values for non-encapsulated (free) docetaxel. The non-encapsulated docetaxel had large volume of distribution with mean Vss ranging values from 47.0 ± 6.3 L/m2 (110 mg/m2 dose) to 104 L/m2 [30 mg/m2 dose; no SD since N = 1]. The Vss values suggest apparent distribution in the whole body water and potential binding to other body tissues. The encapsulated docetaxel had a moderate volume of distribution with mean Vss values ranging from 13.7 ± 3.47 L/m2 (60 mg/m2 dose) to 18.7 ± 3.46 L/m2 (110 mg/m2 dose). The Vss values suggest apparent distribution into the vascular and the interstitial fluid compartments. DocePLUS™ appeared to have enhanced drug exposure as compared to the exposure of Taxotere® as reported in the literature. The CL and T1/2 values determined in the current study are consistent with the values reported in the literature. Docetaxel exposure as measured by the Cmax and AUC in the current study appeared to be higher than the values reported in the literature. In addition, the current study also showed encapsulated docetaxel exposure 2–3× higher than that of corresponding values for (free) docetaxel, which may be attributed to the reduced clearance of encapsulated docetaxel. Consequently, encapsulated docetaxel could be considered as in depo source for non-encapsulated (free) docetaxel.

Antitumor Activity

1 of the 29 evaluable patients demonstrated a partial response as defined by RECIST version 1.1. This patient had non-small cell lung carcinoma previously treated with docetaxel, was enrolled at the MTD, and had a time to disease progression of 30 weeks. 22 patients (75%) had stable disease (SD) as their best response. Among patients with SD, significant treatment-induced tumor size reduction was observed in 4 patients (lung—19.6%, pancreas—12.2%, pancreas—12% and lung—11%). This also includes a pancreatic cancer subject, treated at the MTD, achieving a 29.4% reduction in tumor size from baseline. 8 patients had prolonged SD lasting more than 15 weeks. 2 prostate cancer patients had robust prostate-specific antigen (PSA) response (>95% reduction) following multiple treatment cycles, including 1 patient who was progression free for 54 weeks.  A patient response summary in 20 patients with measurable disease is shown below.

The treatment results achieved with DocePLUS™ were durable and maintained with minimal toxicity.  3 out of a total of 5 patients with prostate cancer were able to receive ≥ 15 cycles of therapy. The maximum number of cycles administered was 21, which occurred in a 74-year old subject with castrate-resistant prostate cancer who was treated with the 30 mg/m2 dose. Three patients with non-small cell lung cancer treated at MTD dose level also received ≥ 5 cycles.

CyclesNumber of Patients Treated
13
2-36
4-56
64
7 or More10

Of the 9 subjects in this study with prior TAXOTERE® exposure, 1 confirmed PR and 5 cases of SD were observed (prostate and pancreatic cancer). This included 2 subjects (one at MTD and one at 60 mg/m2) who had primary Taxotere resistance as evident by previously documented disease progression. When treated with DocePLUS™, they both had stable disease lasting > 30 weeks.

Summary

In the Phase 1 study, DocePLUS™ demonstrated an acceptable tolerability, a favorable PK profile as well as promising antitumor activity that warrants further exploration in larger Phase 2 trials.

References:

REGULATORY PLAN

PLUS THERAPEUTICS intends to develop DocePLUS™ for the treatment of patients with small cell lung cancer (SCLC).

In September 2018, FDA granted DocePLUS™ an orphan drug designation for the treatment of SCLC.

More recently, in July 2019, FDA provided feedback regarding the PLUS THERAPEUTICS’ development of DocePLUS™.  Key feedback from the FDA included that a 505(b)(2) application appears to be an acceptable regulatory path with docetaxel injection as a potentially acceptable listed drug (LD). Furthermore, the FDA agreed that the completed nonclinical studies are sufficient to support the initiation of a clinical trial of DocePLUS™ in patients with platinum-sensitive SCLC who have progressed at least 60 days after initiation of first-line therapy.

PLUS THERAPEUTICS plans to conduct clinical trials in SCLC under its existing, approved Investigation New Drug (IND) application.  These studies will complement the nonclinical proof-of-concept, toxicity, and Phase 1 studies previously conducted with DocePLUS™.

PATENTS

PLUS THERAPEUTICS actively and continually assesses its patenting and enforcement strategy for new product candidates and technologies in both developed and emerging countries to ensure continued innovation and market access and to protect the investments made in research, development, manufacturing, and commercialization.  We also regularly perform systematic reviews of our existing patents to verify a patent’s therapeutic value and to evaluate if a patent should be abandoned or maintained.

Issued

TitleCountryPatent NumberExpiration Date
Protein Stabilized Liposomal Formulations of Pharmaceutical AgentsCanada2505520November 2023
Protein Stabilized Liposomal Formulations of Pharmaceutical AgentsUSA7179484April 2024

Pending

TitleCountryApplication NumberFiling Date
Protein Stabilized Liposomal Formulations of Pharmaceutical AgentsEurope3781768November 2003
Liposomal Taxanes for Treatment of Small Cell Lung CancerUSA62/542993August 2017