On May 4, 2015 CytRx reported an interim analysis from its two ongoing phase 1b aldoxorubicin combination studies pairing aldoxorubicin with either gemcitabine or ifosfamide (Press release, CytRx, MAY 4, 2015, View Source [SID:1234503564]). Both studies combine standard doses of gemcitabine or ifosfamide with escalating doses of aldoxorubicin. The combinations appear to be well tolerated, and even at the lowest dose level of aldoxorubicin (170 mg/m2), impressive tumor responses have been observed so far in patients with bone cancer (osteosarcoma) and a variety of soft tissue sarcomas. As such, aldoxorubicin has the potential when used in combination with other cancer agents to become an important new weapon against chemotherapy resistant cancers.

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"I am very excited so far with both the tolerability and activity of these combinations," said Dr. Sant Chawla, Principal Investigator and Director of the Sarcoma Oncology Center, Santa Monica, CA. "Our first patient with osteosarcoma treated with ifosfamide plus aldoxorubicin had a PET-demonstrated complete tumor response after only five cycles of the combination that has persisted for over six months. Several patients administered the gemcitabine plus aldoxorubicin combination showed tumor shrinkage after only two cycles of treatment, and a patient with advanced cartilage/bone cancer, a rare and deadly cancer, was able to stop all pain medication except Advil and returned to work full time. These results support the further study of these combinations in larger outcome clinical trials."

The first study is an open-label, Phase 1b clinical trial investigating the preliminary safety and activity of ascending doses of aldoxorubicin plus ifosfamide/mesna for the first-line treatment of patients with locally advanced, unresectable, and/or metastatic sarcomas, including bone cancer. Interim results from seven evaluable patients show that the combination of aldoxorubicin plus ifosfamide/mesna was well tolerated. One bone cancer patient achieved a complete tumor response following five treatment cycles. The Company expects to complete dose escalation in this trial in the second half of 2015, and to begin adding sarcoma patients at the maximum well-tolerated dose combination.

The second trial is an open-label, Phase 1b clinical trial investigating the preliminary safety and activity of ascending doses of aldoxorubicin plus gemcitabine in patients with advanced, unresectable, metastatic solid tumors that have either relapsed or were refractory to treatment following at least one prior chemotherapy or immunotherapy regimen, and for which no standard approved therapy exists. Interim results from seven patients show that the combination of aldoxorubicin plus gemcitabine was well tolerated. Tumor shrinkage was observed in three of seven patients following two treatment cycles. One patient with advanced dedifferentiated chondrosarcoma (cartilage/bone cancer), chronic severe pain and inability to function normally demonstrated meaningful quality of life improvements, including stopping prescription narcotic pain medications and returning to full-time work. The Company expects to complete dose escalation in this trial in the second half of 2015, and to begin adding patients with either relapsed pancreatic or ovarian cancer at the maximum well-tolerated dose combination.

"We believe that aldoxorubicin has the potential to be combined with other anti-cancer agents in order to improve patient outcomes for many types of cancer," said Steven A. Kriegsman, Chairman and CEO of CytRx. "These results, which include excellent tolerability and compelling initial signs of activity, even at the lowest dose of aldoxorubicin, provide an opportunity to expand the aldoxorubicin development pipeline and explore additional indications. For aldoxorubicin plus gemcitabine, we are exploring further development of this combination as a treatment for patients with advanced pancreatic or ovarian cancers that have relapsed, or not yet responded, following initial courses of chemotherapy. We are encouraged by these initial results and look forward to providing updates on these studies as they reach completion."

About the Phase 1b Study Design of Aldoxorubicin Plus Ifosfamide/Mesna in Advanced Sarcomas

In this 30-subject, multisite, Phase 1b trial, aldoxorubicin is being administered at escalating doses by intravenous infusion (IVI) on Day 1 every 28 days, and 1 gm/m2/day of ifosfamide and an equivalent dose of mesna will be administered via continuous infusion with a portable at-home pump for up to 14 days every 28 days starting on Day 1 of each cycle, until disease progression, unacceptable toxicity or the patient withdraws consent. The primary objective of the trial is to determine the preliminary safety of administration of aldoxorubicin in combination with ifosfamide in subjects with metastatic, locally advanced, or unresectable STS as measured by the frequency and severity of adverse events (AEs), abnormal findings on physical examination, laboratory tests, vital signs, echocardiograms (ECHO) or multiple-gated acquisition (MUGA) scans, electrocardiogram (ECG) results, and weight. The secondary objective of the trial is to evaluate the activity of aldoxorubicin in combination with ifosfamide/mesna in this population, assessed by overall response rate (ORR), progression-free survival (PFS) and PFS at 4 and 6 months.

About the Phase 1b Study Design of Aldoxorubicin Plus Gemcitabine in Metastatic Solid Tumors

In this 30-subject, multisite, Phase 1b trial, aldoxorubicin is being administered at escalating doses by intravenous infusion (IVI) on Day 1 every 21 days plus 900 mg/m2 gemcitabine on Days 1 and 8 every 21 days until disease progression, unacceptable toxicity or the patient withdraws consent. The primary objective of the trial is to determine the preliminary safety of administration of aldoxorubicin in combination with gemcitabine in subjects with metastatic solid tumors as measured by the frequency and severity of adverse events (AEs), abnormal findings on physical examination, laboratory tests, vital signs, echocardiograms (ECHO) or multiple-gated acquisition (MUGA) scans, electrocardiogram (ECG) results, and weight. The secondary objective of the trial is to evaluate the activity of aldoxorubicin in combination with gemcitabine in this population, assessed by overall response rate (ORR), progression-free survival (PFS), and PFS at 4 and 6 months.

About Bone Cancers (Osteosarcoma, Chondrosarcoma)

Bone cancer is a highly aggressive type of cancer that develops in bone. It starts in immature bone cells (osteoblasts) that normally form new bone tissue. According to the National Cancer Institute, there are approximately 3400 new cases of bone and joint cancer diagnosed each year in the United States, with approximately half of these occurring in children and teens. In addition, the estimated deaths in the U.S. were 1,460 in 2014. Although they can arise in any bone in the body, the most frequent sites are at the ends of the long bones of the legs and arms. In most cases, treatment consists of both chemotherapy and surgery, but patients with metastatic bone cancer continue to have a poor 5-year survival rate (15-30%).

About Aldoxorubicin

The widely used chemotherapeutic agent doxorubicin is delivered systemically and is highly toxic, which limits its dose to a level below its maximum therapeutic benefit. Doxorubicin also is associated with many side effects, especially the potential for damage to heart muscle at cumulative doses greater than 450 mg/m2. Aldoxorubicin combines doxorubicin with a novel single-molecule linker that binds directly and specifically to circulating albumin, the most plentiful protein in the bloodstream. Protein-hungry tumors concentrate albumin, thus increasing the delivery of the linker molecule with the attached doxorubicin to tumor sites. In the acidic environment of the tumor, but not the neutral environment of healthy tissues, doxorubicin is released. This allows for greater doses (3 ½ to 4 times) of doxorubicin to be administered while reducing its toxic side effects. In studies thus far there has been no evidence of clinically significant effects of aldoxorubicin on heart muscle, even at cumulative doses of drug well in excess of 2,000 mg/m2.

On May 4, 2015 BioLineRx reported successful completion of the dose escalation stage of its ongoing Phase 2 study of BL-8040, and commencement of the expansion stage at the optimal dose of this novel treatment for acute myeloid leukemia (AML) (Press release, BioLineRx, MAY 4, 2015, View Source [SID:1234503563]). Top-line results from the study are anticipated in the fourth quarter of 2015.

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Results of the completed dose escalation stage, in which 22 patients participated, showed that all BL-8040 tested doses, up to 1.5 mg/kg, were found to be safe and well tolerated when administered in combination with Ara-C (Cytarabine). Building upon prior interim results, which included doses up to 1.25 mg/kg and were presented at the 2014 American Society for Hematology conference, the data indicate that BL-8040 exhibits robust single-agent activity, with a dramatic decrease in the amount of AML cells in the bone marrow and significant mobilization of these cells into the peripheral blood following two days of BL-8040 monotherapy, as well as direct induction of leukemia cell death. Based on the study’s pharmacodynamic data, 1.5 mg/kg was chosen as the dose for use in the expansion stage of the study. In parallel to initiation of the expansion stage, additional patients will be recruited to assess one higher dose level of BL-8040, in order to further expand the therapeutic window of the drug.

"We are greatly encouraged by these interim results and are excited to commence the final stage of this important trial," said Dr. Kinneret Savitsky, Chief Executive Officer of BioLineRx. "We expect this stage to progress much more quickly than the dose-escalation stage of the trial, which required approval from the data safety monitoring committee before moving to the next dose level. We also expect to open additional sites for this stage of the trial. We look forward with much anticipation to announcing top-line results of the trial, which we expect in the fourth quarter of this year."

Dr. Savitsky continued, "Our expanding BL-8040 platform continues its track record of impressive achievements, including the recently reported successful top-line results from our Phase 1 safety and efficacy study for stem cell mobilization. We expect to provide the full set of results from this study at the European Hematology Association (EHA) (Free EHA Whitepaper) Congress being held next month in Vienna, Austria. In addition, as previously reported, we expect to commence clinical trials for three additional indications for BL-8040 in the next few months."

About BL-8040

BL-8040 is a clinical-stage drug candidate for the treatment of acute myeloid leukemia, as well as other hematological indications. It is a short peptide that functions as a high-affinity antagonist for CXCR4, a chemokine receptor that is directly involved in tumor progression, angiogenesis (growth of new blood vessels in the tumor), metastasis (spread of the disease to other organs or organ parts) and cell survival. CXCR4 is over-expressed in more than 70% of human cancers and its expression often correlates with disease severity. In a Phase 1/2, open-label, dose escalation, safety and efficacy clinical trial in 18 multiple myeloma patients, BL-8040, when combined with G-CSF, demonstrated an excellent safety profile at all doses tested and was highly effective in the mobilization of hematopoietic stem cells and white blood cells from the bone marrow to the peripheral blood. Additionally, in a Phase 1 stem cell mobilization study in healthy volunteers, BL-8040 as a single agent was safe and well tolerated at all doses tested and resulted in efficient stem cell mobilization and collection in all study participants. Importantly, the results of this study support the use of BL-8040 as one-day, single-dose collection regimen, which is a significant improvement upon the current standard of care.

BL-8040 also mobilizes cancer cells from the bone marrow and may therefore sensitize these cells to chemo- and bio-based anti-cancer therapy. Importantly, BL-8040 has also demonstrated a direct anti-cancer effect by inducing apoptosis. Pre-clinical studies show that BL-8040 inhibits the growth of various tumor types including multiple myeloma, non-Hodgkin’s lymphoma, leukemia, non-small cell lung carcinoma, neuroblastoma and melanoma. BL-8040 significantly and preferentially stimulated apoptotic cell death of malignant cells (multiple myeloma, non-Hodgkin’s lymphoma and leukemia). Significant synergistic and/or additive tumor cell killing activity has been observed in-vitro and in-vivo when tumor cells were treated with BL-8040 together with Rituximab, Bortezomib, Imatinib, Cytarabine and the FLT-3 inhibitor AC-220 (in NHL, MM, CML, AML, and AML-FLT3-ITD models, respectively). In addition, the current Phase 2 clinical trial in AML patients has demonstrated robust mobilization and apoptosis of cancer cells. BL-8040 was licensed by BioLineRx from Biokine Therapeutics and was previously developed under the name BKT-140.

About Acute Myeloid Leukemia (AML)

Acute myeloid leukemia (AML) is a cancer of the blood and bone marrow and is the most common type of acute leukemia in adults. According to the American Cancer Society, approximately 14,500 new cases of AML were diagnosed in the United States in 2013, and the median age of AML patients was 66 years old. The frontline treatment for patients with AML includes systemic combination induction chemotherapy. The median survival for patients receiving induction chemotherapy, which is associated with high mortality, is 6-12 months, with shorter survival for patients over the age of 60 or for those with certain gene or chromosome aberrations. The five-year survival rate for AML is 10-30 percent, due to relapsed or refractory disease associated with standard treatments.