Tag Archives: Phase II clinical study results

ENMD-2076 Monotherapy Demonstrates Anti-Cancer Activity in Recurrent, Platinum-Resistant Ovarian Clear Cell Carcinoma

Posted on by

An Aurora A/angiogenic kinase inhibitor named “ENMD-2076” demonstrated anti-cancer activity in recurrent, platinum-resistant epithelial ovarian cancer patients, including three patients with a difficult-to-treat subtype of the disease referred to as “clear cell carcinoma.”

An Aurora A/angiogenic kinase inhibitor named “ENMD-2076” demonstrated anti-cancer activity in recurrent, platinum-resistant epithelial ovarian cancer patients, including three patients with a difficult-to-treat subtype of the disease referred to as “clear cell carcinoma.” The trial drug results were reported in connection with a phase II clinical trial testing of ENMD-2076. The findings associated with ENMD-2076 were published in the January 2013 edition of the European Journal of Cancer.

ENMD-2076 is an orally-active, Aurora A/angiogenic kinase inhibitor with a unique kinase selectivity profile and multiple mechanisms of action. ENMD-2076 has been shown to inhibit a distinct profile of angiogenic tyrosine kinase targets in addition to the Aurora A kinase. Aurora kinases are key regulators of mitosis (cell division), and are often over-expressed in human cancers. ENMD-2076 also targets the VEGFR, Flt-3 and FGFR3 kinases which have been shown to play important roles in the pathology of several cancers.

The phase II trial was an open-label, single-arm Phase II study of single agent ENMD-2076 taken daily (orally). The study enrolled 64 patients, and the progression-free survival (PFS) rate at 6 months was 22%, with a median time-to-progression of 3.6 months. The median number of prior treatment regimens per patient was two. The most common adverse events were fatigue, hypertension and diarrhea, with the most significant events being hypertension and fatigue. Unfortunately, none of the markers of mitotic index or angiogenesis evaluated in the archival tissue samples obtained were predictive of greater benefit or resistance to ENMD-2076 treatment.

Based on the foregoing results, the clinical investigators concluded that ENMD-2076 possesses anti-cancer activity in recurrent, platinum-resistant ovarian cancer, and they observed  toxicities were similar to other protein kinase inhibitors. The clinical investigators also noted that additional studies with ENMD-2076 are warranted, especially in combination with active chemotherapeutic agents in platinum-resistant patients. The investigators added that further work to determine appropriate biomarkers for ENMD-2076 should be incorporated into new clinical studies.

The co-authors of the article include clinical investigators from the Memorial Sloan-Kettering Cancer Center, Indiana University Simon Cancer Center, University of Colorado, and University of Chicago in the U.S., as well as the Princess Margaret Hospital and Campbell Family Institute for Cancer Research in Toronto, Canada.

Ursula Matulonis, M.D., Medical Director, Gynecologic Oncology, Dana-Farber Cancer Institute

Ursula A. Matulonis, M.D., Medical Director, Gynecologic Oncology, Dana-Farber Cancer Institute

Lead study author Dr. Ursula A. Matulonis, who is the medical director of Gynecologic Oncology at the Dana-Farber Cancer Institute, commented on the publication as follows:

“Epithelial ovarian cancer represents the 4th leading cause of cancer deaths among women in the United States. There is unmet medical needs to develop new drugs with fewer side effects and/or better efficacy to improve the quality and duration of life of the patients, especially those whose cancer is resistant to platinum treatment.

ENMD-2076 is a novel small molecule kinase inhibitor with unique combination of mechanisms of action that involve inhibition of several pathways key to tumor growth and survival including angiogenesis, proliferation, and the cell cycle. Based on pre-clinical and Phase 1 clinical studies of ENMD-2076, we believed that the drug candidate may play a role in fitting some of the unmet medical needs. This Phase 2 trial further demonstrates the anti-cancer activity of ENMD-2076 in yet a difficult to treat patient population of platinum-resistant ovarian cancer with tolerable side effects.”

Notably, Dr. Matulonis also commented on the anti-cancer activity of ENMD-2076 in three ovarian clear cell carcinoma patients as follows:

“ENMD-2076 also showed anti-cancer activities in patients with clear cell carcinoma [CCC], a histological subtype considered as chemo-resistant. Two of three [CCC] patients recruited had longer PFS than the median with one patient in stable disease for over two years. As recent reports suggest VEGF is frequently expressed in clear cell cancers, this subtype might be particularly responsive to therapies that incorporate VEGF inhibition. Further clinical evaluations of ENMD-2076 may therefore be warranted in this patient subset either as a single agent or in combinations.” [emphasis added]

Ken Ren, Ph.D., EntreMed’s Chief Executive Officer, further commented:

“We are very pleased and honored to have this Phase 2 trial data published in such an esteemed journal. This is a further endorsement of the global medical and science community on the clinical and scientific value of ENMD-2076 in ovarian cancer treatment. We truly believe that ENMD-2076 may potentially offer unique and competitive advantages for unmet medical needs in such difficult to treat oncology indications including platinum-resistant and/or clear cell ovarian cancer in improving the patients’ quality and duration of life. We are committed to the global clinical development of ENMD-2076 for cancer patients who might benefit from its therapy. With the support of clinical investigators like Dr. Matulonis, their commitment and dedication, and the support from our long term shareholders, we are confident that we can achieve our goal.”

About EntreMed

EntreMed, Inc. is a clinical-stage pharmaceutical company employing a drug development strategy primarily in the United States and China to develop targeted therapeutics for the global market. Its lead compound, ENMD-2076, a selective angiogenic kinase inhibitor, has completed several Phase 1 studies in solid tumors, multiple myeloma, and leukemia, and is currently completing a multi-center Phase 2 study in ovarian cancer. EntreMed, Inc. recently initiated a dual-institutional Phase 2 study of ENMD-2076 in triple-negative breast cancer. Additional information about EntreMed is available on the Company’s web site at www.entremed.com.

About ENMD-2076

ENMD-2076 is an orally-active, Aurora A/angiogenic kinase inhibitor with a unique kinase selectivity profile and multiple mechanisms of action. ENMD-2076 has been shown to inhibit a distinct profile of angiogenic tyrosine kinase targets in addition to the Aurora A kinase. Aurora kinases are key regulators of mitosis (cell division), and are often over-expressed in human cancers. ENMD-2076 also targets the VEGFR, Flt-3 and FGFR3 kinases which have been shown to play important roles in the pathology of several cancers. ENMD-2076 has shown promising activity in Phase 1 clinical trials in solid tumor cancers, leukemia, and multiple myeloma. ENMD-2076 is currently completing a Phase 2 trial for ovarian cancer. EntreMed, Inc. recently initiated a dual-institutional Phase 2 study of ENMD-2076 in triple-negative breast cancer.

ENMD-2076 received orphan drug designation from the United States Food and Drug Administration (FDA) for the treatment of ovarian cancer, multiple myeloma and acute myeloid leukemia (AML). In the United States, the Orphan Drug Act is intended to encourage companies to develop therapies for the treatment of diseases that affect fewer than 200,000 people in this country. Orphan drug designation provides seven years of market exclusivity that begins once ENMD-2076 receives FDA marketing approval. It also provides certain financial incentives that can help support the development of ENMD-2076.

Citation:

Matulonis UA, Lee J, Lasonde B, et. al. ENMD-2076, an oral inhibitor of angiogenic and proliferation kinases, has activity in recurrent, platinum resistant ovarian cancer. Eur J Cancer. 2013 Jan;49(1):121-31.doi:10.1016/j.ejca.2012.07.020. PubMed PMID: 22921155.

Additional Source:

Dana-Farber Cancer Institute’s Ursula A. Matulonis, M.D. Article on EntreMed’s ENMD-2076 Published in the European Journal of Cancer, EntreMed, Inc. Press Release, Sept. 6, 2012.

ENMD-2076 Phase II Ovarian Cancer Clinical Trial Protocol Summary:

A Phase 2 Study of Oral ENMD-2076 Administered to Patients With Platinum Resistant Ovarian Cancer, ClinicalTrials.gov Identifier: NCT01104675 (study ongoing, but not recruiting patients).

GOG Reports on Evaluation of Pemetrexed in Treatment of Recurrent Platinum-Resistant Ovarian Cancer

Posted on by

A phase II Gynecologic Oncology Group (GOG) clinical study found that pemetrexed (Altima®)-an antifolate antineoplastic agent that disrupts folate-dependent cell replication metabolic processes-is sufficiently active in the treatment of recurrent platinum-resistant ovarian cancer to warrant further investigation.  “Thus [pemetrexed] should be considered for combination with other agents, especially carboplatin, in first-line therapy,” said David Miller, M.D., F.A.C.S. (University of Texas Southwestern Medical Center, Dallas, USA) and colleagues.

millerdavid

David Miller, M.D. F.A.C.S., Professor, Gynecologic Oncology, University of Texas Southwestern Medical Center

A phase II Gynecologic Oncology Group (GOG) clinical study found that pemetrexed (Altima®)-an antifolate antineoplastic agent that disrupts folate-dependent cell replication metabolic processes-is sufficiently active in the treatment of recurrent platinum-resistant ovarian cancer to warrant further investigation.  “Thus [pemetrexed] should be considered for combination with other agents, especially carboplatin, in first-line therapy,” said David Miller, M.D., F.A.C.S. (University of Texas Southwestern Medical Center, Dallas, USA) and colleagues.

The purpose of the GOG study was to estimate the antitumor activity of pemetrexed in patients with persistent or recurrent, platinum-resistant epithelial ovarian or primary peritoneal cancer and to determine the nature and degree of toxicities.  The patients that participated in the study experienced disease progression on platinum-based primary chemotherapy or recurred within 6 months. Pemetrexed at a dose of 900 mg/m2 was administered as an intravenous infusion over 10 minutes every 21 days. Dose delay and adjustments were permitted for toxicity. Treatment was continued until disease progression or unacceptable adverse effects.  From July 6, 2004, to August 23, 2006, 51 patients enrolled in the study.  A total of 259 cycles (median, four; range one to 19 cycles) of pemetrexed were administered, with 40% of the patients receiving six or more cycles.

According to the investigators, the study produced the following results:

  • No treatment -related deaths were reported;
  • Eighteen patients (38%) had progressive disease. Three patients (6%) were not assessable;
  • One patient (2%) had a complete response (CR) and nine patients (19%) had partial responses (PRs), with a median duration response of 8.4 months. Seventeen patients (35%) had stable disease (SD) for a median of 4.1 months. Clinical benefit rate (CR + PR + SD) was 56%; and

Based upon the foregoing results, the investigators noted that pemetrexed “exhibited activity more favorable than that seen in other agents that have been test in first-line combinations by the GOG.” Pemetrexed, according to the investigators, has sufficient activity in the treatment of recurrent platinum-resistant ovarian cancer at the dose and schedule tested to warrant further investigation.

Sources:

Small Phase II Study Tests the Use of Fulvestrant in the Treatment of Recurrent Epithelial Ovarian Cancer

Posted on by

… University of Minnesota researchers evaluated the use of fulvestrant [Faslodex®] in women with recurrent ovarian or primary peritoneal cancer. …Using modified-RECIST criteria 13 patients (50%) achieved SD …[T]he University of Minnesota researchers concluded that fulvestrant is well-tolerated and efficacious. The researchers also noted that objective response rates are low, but disease stabilization was common.

It is well-known that the goal of treating recurrent ovarian cancer is disease control while minimizing toxicity. Previously, Fulvestrant (Faslodex®), a novel estrogen receptor (ER) antagonist, was proven clinically beneficial and well-tolerated in treating recurrent breast cancer. If a pathologist determines that a women’s ovarian cancer biopsy is estrogen receptor positive (ER+), there is a possibility that she may respond to anti-estrogen therapy.

On this basis, University of Minnesota researchers evaluated the use of fulvestrant in women with recurrent ovarian or primary peritoneal cancer. Patients with ER+, multiply recurrent ovarian or primary peritoneal carcinoma were eligible for trial enrollment if (i) they had measurable disease according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria, or (ii) an abnormal and rising CA-125 blood test measurement. Treatment consisted of single agent fulvestrant, 500 mg IM (intramuscular) on Day 1, 250 mg IM on Day 15, and 250 mg IM on Day 29 and every 28 days thereafter until the patient experienced intolerance or disease progression. Disease response was assessed by monthly physical exams and CA-125 levels as well as bimonthly CT scans. The clinical trial primary endpoint was “clinical benefit” (CB) (i.e., CB=complete response (CR) + partial response (PR) + stable disease (SD)) at 90 days).

Pursuant to the phase II fulvestrant clinical trial, the study researchers reported the following:

  • Thirty-one women were enrolled and 26 women (median age of 61) met inclusion criteria and received at least one dose;
  • Patients received a median of 5 prior chemotherapeutic regimens (range: 2-13) prior to enrollment;
  • One patient experienced CR (4%), one patient experienced PR (4%), and 9 patients experienced SD (35%) using modified-Rustin criteria (CA-125 level);
  • Using modified-RECIST criteria 13 patients (50%) achieved SD;
  • The median time to disease progression was 62 days (mean 86 days); and
  • Grade 1 toxicity included headache (1 patient) and bromidrosis (2 patients).

Based upon the foregoing results, the University of Minnesota researchers concluded that fulvestrant is well-tolerated and efficacious. The researchers also noted that objective response rates are low, but disease stabilization was common.

Primary Source:  A phase II study of fulvestrant in the treatment of multiply-recurrent epithelial ovarian cancer; Argenta PA, Thomas SG, Judson PL et. al., Gynecol Oncol. 2009 Feb 22. [Epub ahead of print]

M.D. Anderson Researchers Find GM-CSF and rIFN-gamma1b Plus Carboplatin Effective For the Treatment of Recurrent, Platinum-Sensitive Ovarian Cancer

Posted on by

Researchers working in the Gynecologic Oncology Department of The University of Texas M.D. Anderson Cancer Center, reported Phase II clinical study results from their evaluation of the use of carboplatin, granulocyte-macrophage colony-stimulating factor (GM-CSF) and recombinant interferon gamma 1b (rIFN-gamma1b) in women with recurrent, platinum-sensitive ovarian, fallopian tube and primary peritoneal cancer. …

Researchers working in the Gynecologic Oncology Department of The University of Texas M.D. Anderson Cancer Center, reported Phase II clinical study results from their evaluation of the use of carboplatin, granulocyte-macrophage colony-stimulating factor (GM-CSF) and recombinant interferon gamma 1b (rIFN-gamma1b) in women with recurrent, platinum-sensitive ovarian, fallopian tube and primary peritoneal cancer.

As part of this Phase II clinical study, patients with recurrent, platinum-sensitive ovarian, fallopian tube or primary peritoneal cancer were treated with subcutaneous GM-CSF and rIFN-gamma1b before and after intravenous carboplatin until their disease progressed or unacceptable toxicity occurred. All patients had measurable disease and a chemotherapy-free interval >6 months. Response was determined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria and CA 125 blood serum levels. Between 2003 and 2007, 59 patients received a median of 6 cycles of therapy (range, 1 to 13 cycles). The median patient age at enrollment was 61 years (range, 35 to 79 years). The median patient time to disease progression prior to clinical study enrollment was 11 months (range, 6 to 58 months).

The M.D. Anderson researchers reported the following results:

Based upon the foregoing results, the researchers concluded that the pre- and post-carboplatin cytokine regimen resulted in a reasonable response and a hematologic profile that could invite further evaluation of its components in the treatment of patients with ovarian cancer.

Primary Source:  A phase II study of GM-CSF and rIFN-gamma1b plus carboplatin for the treatment of recurrent, platinum-sensitive ovarian, fallopian tube and primary peritoneal cancer; Schmeler KM, Vadhan-Raj S, Ramirez PT et. al., Gynecol Oncol. 2009 Mar 3. [Epub ahead of print].