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. Schedule your 30 min Free 1stOncology Demo! "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."
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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.