Clinical Development

Observations from previous preclinical and clinical studies suggest that gallium-containing compounds may be broadly useful for diseases that are characterized by loss of calcium from bone and reduction in bone mass.  Clinical conditions that are associated with these features are outlined in the Clinical Plans tab.

Genta’s oral gallium compounds are investigational agents undergoing testing to evaluate safety and efficacy in the treatment of various conditions associated with bone loss. Studies are currently planned to examine the potential role of these compounds in a variety of clinical indications.

• Clinical Plans
• Completed Trials

• Similar to cancer-related hypercalcemia, skeletal erosion due to bone metastases is caused by factors secreted by cancer cells that act either focally or systemically to stimulate osteoclast-mediated bone resorption.  The concept of using medical therapies, especially bisphosphonates, as adjuncts to traditional anticancer treatment in order to strengthen bone against erosion is now well established.  Ideally, such therapy should not only minimize further bone loss but also restore bone that has been previously eroded.  Some of the clinical work with the active ingredient is summarized in the Completed Trials tab.

  Cancer-Related Hypercalcemia

  This condition most commonly occurs in patients with advanced cancer.  In hypercalcemia, the rate of loss of bone calcium becomes so rapid that the blood concentration of calcium increases to levels that are acutely life threatening if left untreated.  The citrated solution of gallium nitrate (Ganite^®) is approved for marketing by Genta in the United States for treatment of patients with cancer-related hypercalcemia that is resistant to hydration.

  Bone Metastases

  Bone is one of the most common sites of cancer metastases.  This problem is particularly prevalent in the most common types of cancers, including myeloma, and cancers of the breast, prostate, lung, and head and neck.  Bone metastases lead to erosion and loss of bone strength.  Common complications include pain, immobility, fractures, spinal cord compression, paralysis, and hypercalcemia.

  Paget's Disease

  This condition is quite prevalent in older persons and is characterized by disordered bone formation and resorption.  These processes eventually lead to pain, hearing loss, skeletal deformities, and fractures.

  Osteoporosis

  This disorder is the most common bone disease, and it affects both men and women.  Unlike hypercalcemia (which can be acutely life-threatening within several days), bone loss in osteoporosis occurs over a period of years until bone strength is sufficiently reduced such that the risk of sudden fracture becomes very high.  The most common sites of osteoporotic fractures are the hips, wrists, and vertebrae.

  The safety and efficacy of an oral gallium compound have not been established for any use.

• Cancer-Related Hypercalcemia

  The active ingredient, administered parenterally as a citrated solution of gallium nitrate (Ganite^®), has been extensively studied in cancer-related hypercalcemia, and the drug is approved for marketing in this indication in the United States.   In addition to Phase 1-2 studies, three randomized double-blind trials have been completed comparing gallium nitrate with calcitonin (Calcimar^®), etidronate (Didronel^®; Proctor & Gamble), and pamidronate (Aredia^®; Novartis, Inc).

  Bone Metastases

  Similar to cancer-related hypercalcemia, skeletal erosion due to bone metastases is caused by factors secreted by cancer cells that act either focally or systemically to stimulate osteoclast-mediated bone resorption.  The concept of using medical therapies, especially bisphosphonates, as adjuncts to traditional anticancer treatment in order to strengthen bone against erosion is now well established.  Ideally, such therapy should not only minimize further bone loss but also restore bone that has been previously eroded.  Some of the clinical work with the active ingredient is summarized below.

  Pilot Study in Bone Metastasis:  In a preliminary study of patients with osteolytic metastases (not restricted to tumor type), gallium was administered by IV infusion to 22 patients.

  Phase 2 Study of Low Repeat-Doses in Multiple Myeloma:  In a randomized trial, patients receiving stable chemotherapy were randomized to receive gallium (administered by low-dose subcutaneous [SC] injection) or no additional treatment for six months.  Gallium was administered on a schedule of 2 weeks on/2 weeks off for 6 months.  Patients randomized to no gallium during the initial period were crossed over after 6 months.  The principal outcome determinant was the measurement of total-body calcium content using neutron activation analysis, a highly sensitive technique.

  Phase 2 Studies of Low Repeat-Doses in Breast Cancer:  Two pilot studies evaluated the safety and efficacy of low-dose gallium in breast cancer patients with bone metastases.  In a multicenter study, 25 patients were randomized to receive a range of doses (0.25 to 0.75 mg/kg, equal to 10 to 30 mg/m²) injected SC on a continuous once-per-day basis (rather than cyclically) for four months.  In a second study, 16 patients were randomized to receive one of four schedules: no treatment; high-dose intermittent (similar to the myeloma study); low-dose continuous (20 mg/m²/day); or low-dose intermittent (20 mg/m²/day for 2 weeks on/2 weeks off).

  Paget's Disease

  Paget's disease of bone is characterized by abnormally accelerated bone turnover that is driven by excessive osteoclastic resorption and irregular bone remodeling.  The extent and severity of Paget's disease correlates with serum levels of the enzyme alkaline phosphatase (a measure of osteoblastic activity), as well as urinary excretion of hydroxyproline (an index of bone matrix resorption) and other products of bone breakdown.  Paget's disease is a prevalent life-long condition that may affect up to 5% of the adult population older than age 40.  However, only a minority of patients usually require therapy.  Three clinical studies have been completed using short-term treatment with gallium as treatment for Paget's disease.

  Phase 1 Study in Paget's Disease:  The goal of this initial study was to evaluate whether a brief course of treatment could reduce biochemical parameters of accelerated bone turnover.  Five patients were entered into 1 of 3 dose schedules: 2.5 mg/kg/day (100 mg/m²/d) by continuous IV infusion for seven days; 0.5 mg/kg/day (20 mg/m²/day) for 14 days by SC injection; and 0.25 mg/kg/day (10 mg/m²/day) by SC injection for 14 days.

  Phase 2 Study in Paget's Disease:  In a small study at Ohio State University, a single course of therapy at a dose of 100 mg/m²/day was given for 5 consecutive days as a continuous IV infusion.

  Randomized Phase 1-2 Study in Paget's Disease:  A randomized, multi-center Phase 1-2 study was initiated that examined several different low-dose schedules (including a "no effect" dose).  Patients received the drug by single SC injection daily for 2 weeks, followed by 4 weeks of no treatment, and this treatment cycle was then repeated once.  Biochemical parameters of disease activity at 12 weeks were selected as end-points.  In this study, 49 patients were randomly assigned to receive 0.05 mg/kg/day (the "no effect" level) (17 patients), 0.25 mg/kg/day (17 patients), or 0.5 mg/kg/day (15 patients).

  Osteoporosis

  The responses observed in other disorders characterized by accelerated bone loss have suggested that gallium may be useful in the treatment and prevention of osteoporosis.  To date, only a single study in osteoporosis has been performed and extensive clinical testing is required to determine safety and efficacy.

  Pilot Study by IV Infusion in Women with Post-Menopausal Osteoporosis:  Four post-menopausal women were followed over a 15-day period in a metabolic ward.  This study was divided into three discrete periods: a 5-day baseline period; a 5-day treatment period at a dose of 100 mg/m²/day by continuous IV infusion; and a 5-day post-treatment period.

  The safety and efficacy of an oral gallium compound have not been established for any use.