A Phase 2 Trial of Ponatinib in Philadelphia Chromosome–Positive Leukemias.


BACKGROUND

Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor–refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph-positive ALL).

METHODS

We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months.

RESULTS

Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event.

CONCLUSIONS

Ponatinib had significant antileukemic activity across categories of disease stage and mutation status.

 

Source: NEJM

 

Sunitinib Maintenance After Chemotherapy Improves Progression-Free Survival for Extensive-Stage Small Cell Lung Cancer.


After standard chemotherapy, maintenance therapy with sunitinib delayed relapse by approximately 1.5 months compared with placebo for patients with extensive-stage small cell lung cancer (SCLC), according to new findings from a phase II trial.

Dr. Neil Ready, MD, PhD, of the Duke Cancer Institute in Durham, North Carolina, presented results from the randomized, phase II Cancer and Leukemia Group B (CALGB) 30504 trial (Ready N et al., 2013) at the 2013 American Society of Clinical Oncology (ASCO) annual meeting in Chicago, Illinois.

Sunitinib is an oral, multitargeted receptor tyrosine kinase (RTK) inhibitor that shows potent and selective activity against vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (KIT), and other molecular targets implicated in tumor growth and angiogenesis. Sunitinib is currently approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor. Although sunitinib and other RTK inhibitors have been studied extensively in non-small cell lung cancer (NSCLC) (Gridelli C et al.), few studies have examined sunitinib in SCLC.

CALGB 30504 Study Design

The CALGB 30504 trial began in 2007 as a phase I trial of concurrent therapy with sunitinib and standard chemotherapy in untreated extensive-stage SCLC. The concurrent regimen was not feasible, however, due to the risk of grade 5 neutropenia (Ready N et al., 2010). In 2008, the CALGB 30504 protocol was amended to a randomized phase II trial designed to evaluate maintenance sunitinib following chemotherapy. In the current analysis, 85 patients received 4-6 cycles of standard-dose chemotherapy with cisplatin/etoposide or carboplatin/etoposide every 21 days. Patients were randomly assigned to maintenance therapy with sunitinib 37.5 mg/day (n = 44) or placebo (n = 41) until disease progression. Crossover to sunitinib maintenance was permitted in the placebo arm at disease progression.

The median patient age was 60 years (range, 39-77 years). The majority of patients (76.5%) completed 6 cycles of chemotherapy; 26% received cisplatin and 74% received carboplatin. Among patients with a complete or partial response (n = 78), 34 patients (44%) received prophylactic cranial irradiation 4 to 6 weeks after completing chemotherapy.

Patients completed a median of two cycles of maintenance therapy (range, one to 17 cycles). In the sunitinib arm, 68% of patients completed 1 to 4 cycles, while 23% completed 5 to 8 cycles. Four patients (9%) completed 9 or more cycles of sunitinib maintenance. The crossover rate was high, with 40% of patients in the placebo group initiating sunitinib following disease progression.

Improved Progression-Free Survival

The CALGB 30504 trial met its primary endpoint of improved progression-free survival after chemotherapy with maintenance sunitinib. The median progression-free survival was 3.77 months in the sunitinib maintenance group, compared with 2.30 months in the placebo group (HR, 1.53; P = 0.037).

Despite the high crossover rate, maintenance sunitinib showed a trend toward improved overall survival compared with placebo. The median overall survival was 8.95 months in the sunitinib group and 6.89 months in the placebo arm (HR, 1.17; P = 0.27).

Evidence of Single-Agent Activity

An analysis of tumor size before and after crossover to sunitinib in six patients with disease progression in the placebo group also demonstrated the single-agent antitumor activity of sunitinib. In the 6 to 12 weeks prior to crossover, the tumors were exhibiting rapid growth. Following crossover to sunitinib, tumor growth slowed in each case, and some tumors decreased in size.

In another case, the pattern of tumor response during chemotherapy and maintenance provided additional support for single-agent activity with sunitinib. The patient showed a partial response to chemotherapy, which plateaued between cycles 4 and 6, but converted to a complete response during sunitinib maintenance. The complete response was maintained without progression for 15 cycles (45 weeks) of maintenance therapy.

Safety Findings

Maintenance sunitinib appeared safe and feasible at this dose. During maintenance, 46.5% of patients in the sunitinib group reported at least 1 grade 3/4 adverse event, compared with 19.5% of patients in the placebo group. The most common grade 3/4 adverse events during sunitinib maintenance were fatigue (19%), neutropenia (14%), leukopenia (7%), thrombocytopenia (7%), and hyponatremia (5%). Grade 4 events included gastrointestinal hemorrhage (n = 1) and pancreatitis (n = 1).

Next Steps

A biomarker analysis of blood samples is being planned, with the goal of identifying prognostic and predictive markers that may guide the selection of patients for maintenance therapy. A randomized phase III trial is being proposed to test the hypothesis that maintenance sunitinib after standard chemotherapy improves survival in patients with extensive-stage SCLC.

Dr. Ready explained the rationale for additional studies of maintenance sunitinib. “We felt that the [phase II] results were consistent with the hypothesis that there could be a 2-month or more improvement in overall survival with maintenance sunitinib in this setting. We feel that it is reasonable to consider a phase III trial to test that hypothesis,” Dr. Ready said.

Source: The oncologist

 

Current and Future Options for Targeting Activated Kinases in Acute and Chronic Leukemias

Contributors: Anna Azvolinsky, PhD, Anne Jacobson, MPH, CCMEP, CMPP

Tyrosine kinase oncogenes such as BCR-ABL and FLT3 are commonly mutated and activated in acute and chronic myeloid leukemias. The development of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of chronic myelogenous leukemia (CML) and provided new treatment options for patients with chronic myeloproliferative neoplasms and acute leukemias. In a special session at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting on the role of targeted therapy in acute and chronic leukemias, experts discussed the current clinical issues and future opportunities associated with the targeted inhibition of aberrant signaling pathways that drive the development and progression of these malignancies.

Chronic Myelogenous Leukemia

Resistance to BCR-ABL-targeted therapy in patients with CML arises through an array of potential mechanisms, ranging from non-specific multidrug resistance to inherent BCR-ABL genetic alterations. Michael J. Mauro, MDof the Knight Cancer Institute, Oregon Health & Science University, in Portland, Oregon, discussed targeted approaches to managing treatment resistance in patients with CML.

In 2001, the approval of imatinib, the BCR-ABL kinase inhibitor, launched a new area of targeted therapy for CML. Imatinib has been so successful that it has grown to become the targeted therapy all other therapies want to emulate—oncologists often aspire to finding the “imatinib” of other cancer types. As of 2013, five targeted agents are currently available for CML, including two agents, bosutinib and ponatinib, that joined the salvage treatment armamentarium in 2012.

After more than a decade of experience with imatinib in CML, the oncology community has gained critical insight about the development and progression of treatment resistance, with potential implications for other targeted therapies. Importantly, resistance to imatinib is a function both of time and disease volume. Early reduction of disease burden is associated with the reduction or elimination of unstable clones, leading to a reduction in the risk of relapse. Timely cytogenetic and molecular response is a strong predictor of functional cure, which is defined as the absence of meaningful proliferation even after treatment is stopped.

Options for patients who show early resistance to imatinib (e.g., BCR-ABL/ABL >10% at 3 months) include switching to another tyrosine kinase inhibitor based on mutational analysis, evaluating candidacy for stem cell transplant, or referring the patient to a clinical trial. Ongoing trials will evaluate the utility of various approaches to early resistance, including immediate versus delayed switch to an alternate targeted regimen. Treatment selection is further individualized based on a tolerability profile and likelihood of treatment adherence. Among current options, nilotinib, dasatinib, and bosutinib are proven salvage options with promising activity in the front-line setting. Ponatinib also represents a compelling salvage option, particularly for patients with heavily pretreated CML who have stopped responding to all other therapies. A phase III trial comparing ponatinib with imatinib in patients with newly diagnosed chronic-phase CML is currently underway.

Chronic Myeloproliferative Neoplasms

Targeted therapy is rapidly changing the treatment landscape for chronic myeloproliferative neoplasms, including primary myelofıbrosis (MF), essential thrombocytopenia (ET), and polycythemia vera (PV). Following the identification of the JAK2V617F mutation in 2005, the first JAK1/2-targeted therapy was approved just six years later, in 2011. Claire Harrison, DM of the NHS Foundation Trust in the UK, discussed the current standard of care for primary MF, post-ET/PV MF, and other myeloproliferative neoplasms in the era of JAK1/2 inhibitor therapy.

Ruxolitinib was the first oral, selective JAK1/2 inhibitor approved for the treatment of intermediate- and high-risk MF, based on substantial reduction in spleen size and improvements in other constitutional symptoms and quality of life in the phase III COMFORT-1 and COMFORT-2 trials. To date, treatment with ruxolitinib has not resulted in any molecular remissions, although there is hope for the concept of a ‘cure’ with targeted therapy alone. In current practice, allogeneic hematopoietic stem cell transplant is the only curative treatment for patients with MF. Other limitations of current systemic treatment options in MF include concerns about the induction of leukemia as well as the inability to reduce late myeloid transformation.

Building on the success of ruxolitinib, other JAK-targeted inhibitors in development include SAR302503, a selective JAK2 inhibitor; pacritinib, an oral, once-daily, highly selective inhibitor of JAK2 and FMS-like tyrosine kinase 3 (FLT3); and CYT387, an oral JAK1/2 inhibitor. Future clinical trials in this setting may focus on regimens designed to improve the hematologic toxicity profile of current JAK1/2 inhibitor therapy or improve treatment efficacy via the use of novel JAK1/2 inhibitors alone or in combination with other targeted agents, such as histone deacetylase (HDAC), phosphatidylinositol 3 (PI3)-kinase, and smoothened pathway inhibitors.

Acute Leukemia

Advances in the molecular profiling of acute leukemia, particularly the role of activating mutations that result in signaling molecule alterations, may introduce new opportunities for targeted therapy. Neil Shah, MD, PhD of the University of California, San Francisco, discussed the evolving rationale for kinase inhibition in the treatment of acute leukemia.

Acute leukemia is frequently associated with activating mutations in signaling molecules. Kinase inhibitors provide an effective, well-tolerated tool to substantially reduce the burden of disease and, when combined with chemotherapy, improve cure rates in patients with acute myeloid leukemia (AML). The number of possible combination regimens with other targeted agents is growing as novel pathway inhibitors are being developed. Performing detailed molecular analyses of tumor samples is becoming more feasible, and promises to facilitate the personalized selection of rational targeted therapies and combination regimens in the near future.

Several kinase inhibitors are in development for AML, but early stage results lag behind the advances seen in the CML setting. Many of the targeted multikinase inhibitors currently under development in AML may have a role as bridge therapy, providing patients the time to transition to a potentially curative stem cell transplant.

The key obstacle in the development of targeted agents for AML is a lack of a known dominant driver mutation. The most common mutation appears to be a tandem repeats of the activating mutations of the FLT3 receptor tyrosine kinase in about a quarter of patients. Agents such as quizartinib and crenolanib are in clinical trials, but rapid relapse is common. “FLT3 may be a passenger rather than a driver mutation [in AML] and not worth targeting,” saidDr. Shah. Inhibitors of KIT, JAK2, mTOR, and MEK are also under evaluation in AML, but their potential antitumor activity in patients who do not harbor mutated kinases is unknown.

Incorporating next-generation molecular sequencing tools into studies of targeted therapeutics will advance the use of personalized treatment in acute leukemia. Continued participation of patients with AML and other malignancies in clinical trials is strongly encouraged, Dr. Shah said.

Source: The oncologist

 

 

 

 

 

 

 

 

 

Turning Traditional Medicine Into Cancer Drugs.


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Quite a few substances used in traditional medicine in China or other countries have received Food and Drug Administration (FDA) approval as cancer drugs… and their numbers are growing.  Some examples are:

Arsenic trioxide, made from arsenic sulfide ore, has been used therapeutically for more than 2,400 years. Following promising reports from China, the agent was tested in clinical trials and received FDA approval in 2000 for patients with acute promyelocytic leukemia who have not responded to other therapies or whose disease has recurred.

Camptothecin, isolated from the bark and stem of a tree native to China, was long used as a cancer treatment in traditional Chinese medicine. When preliminary clinical trials of the compound showed encouraging results in patients with leukemia, chemists made synthetic versions that retain its anticancer properties while reducing its harsh side effects. Two of these synthesized versions, or analogues, have been approved for the treatment of chronic lymphocytic leukemia.

Podophyllotoxin, isolated from the Mayapple plant that grows in forests in the eastern United States, has a long history as a medicinal agent. A gel made from the compound is used to treat certain kinds of warts, and a synthetic version is used to treat lung cancertesticular cancer,lymphoma, and certain forms of leukemiaand sarcomas.

Vinca alkaloids were derived from the Madagascar periwinkle plant and, according to folklore, were useful in treating diabetes. Scientific testing found they had no antidiabetic properties but could extend the lives of mice with certain forms of leukemia. Synthesized forms of the alkaloids include two of the most common chemotherapy agents in use today, vincristine and vinblastine. Cancers treated with vinca alkaloid-derived drugs include acute leukemia, neuroblastoma,  Wilms tumorHodgkin and non-Hodgkin lymphomas,breast cancermelanoma, and uterine cancer.

Homoharringtonine, which comes from an evergreen shrub indigenous to China called Plum Yew or Cowtail Pine, was approved by the FDA last year for the treatment of adult patients with chronic myelogenous leukemia (CML) who aren’t helped by agents known as kinase inhibitors.

Indirubin, extracted from the indigo plant, is part of a traditional Chinese preparation used to treat CML. Laboratory and animal studies suggest it may be an effective treatment for patients, but clinical trials have not yet been conducted.

Natural compounds from Chinese medicine currently being studied as potential cancer drugs include astragulus (a large family of herbs and shrubs); scutellaria (flowering plants of the mint family, used in traditional Chinese medicine to strengthen the immune system); and indigofera (a large family of flowering plants, used to alleviate pain).

Some naturally-derived agents are used as stand-alone treatments; others are part of combined therapies. Because some natural therapies can decrease the effect of chemotherapy drugs, it’s important for patients to inform their physicians of any alternative treatments they are using.

Source:Dana Faber

FDA Approves New Drug to Treat Chronic Myelogenous Leukemia.


The Food and Drug Administration has approved bosutinib (Bosulif) to treat chronic myelogenous leukemia (CML), a blood and bone marrow disease that usually affects older adults. Bosutinib is intended for patients with chronic, accelerated, or blast phase Philadelphia chromosome-positive CML who are resistant to or who cannot tolerate other therapies, including imatinib (Gleevec).

Most people with CML have a chromosomal aberration called the Philadelphia chromosome, which causes the bone marrow to make an abnormal tyrosine kinase enzyme called Bcr-Abl. This enzyme promotes the proliferation of abnormal and unhealthy infection-fighting white blood cells called granulocytes. Bosutinib is a tyrosine kinase inhibitor (TKI) that works by blocking Bcr-Abl signaling.

Bosutinib’s safety and effectiveness were evaluated in a clinical trial involving 546 adults with chronic, accelerated, or blast phase CML. All of the patients had been previously treated with at least one TKI, either imatinib or imatinib followed by dasatinib (Sprycel) and/or nilotinib (Tasigna).

Among patients with chronic phase CML, 34 percent of patients who had been treated previously with imatinib and 27 percent of those who received more than one prior TKI achieved a major cytogenetic response within 24 weeks.

Among patients with accelerated phase CML who had received at least one prior TKI, 30 percent had their blood counts return to the normal range (a complete hematologic response) by week 48, and 55 percent achieved a complete hematologic response, no evidence of leukemia, or return to chronic phase (an overall hematologic response) by week 48. Among patients with blast phase CML who had received at least one prior TKI, 15 percent had a complete hematologic response and 28 percent an overall hematologic response by week 48.

The most common side effects observed in those receiving bosutinib were diarrhea, nausea, a low level of platelets in the blood, vomiting, abdominal pain, rash, anemia, fever, and fatigue.

Source: NCI