Hematology Pipeline: Baby Steps After a Giant Leap

There are thousands of clinical studies in progress for hematologic malignancies, but many are in phase I or II trials, so it may be some time before the most promising compounds add new weapons to the hematology armamentarium, where they are sorely needed.

More than 1 million people suffer from a hematologic malignancy in the United States, and every year another 148,000 men, women, and children are diagnosed with lymphoma, leukemia, or myeloma.

Marshall A. Lichtman, MD

“We are still relying principally on the same two drug types to treat acute myeloid leukemia (AML) that we used 40 years ago: cytarabine and an anthracycline antibiotic such as daunomycin,” said Marshall A. Lichtman, MD, professor in the departments of Medicine, Hematology/Oncology, and Biochemistry and Biophysics at the University of Rochester School of Medicine and Dentistry in New York. “This demonstrates the need for a broad and aggressive research program, new paradigms, and genius,” to find new therapies for these cancers.

The approval of imatinib (Gleevec, Novartis) in 2001 was a giant leap forward in the treatment of malignancies in which the ABL gene is mutated, resulting in a mutant tyrosine kinase (TK). This mutation occurs in chronic myeloid leukemia (CML) and acute leukemias. Imatinib’s clinical and financial success, as well as the success of the second-generation nilotinib (Tasigna, Novartis) and dasatinib (Sprycel, Bristol-Myers Squibb), which target the mutant ABL TK to stop the proliferation of white cells in certain leukemias and permit restoration of normal blood cell production, encouraged pharmaceutical companies to invest in blood cancer research.

It is difficult to pinpoint exactly how much money companies are spending on developing therapies for hematologic malignancies, but several large companies, including Pfizer, Genentech, Novartis, and Bristol-Myers Squibb, have dedicated parts of their research and development budgets to finding treatments for blood cancers.

The National Cancer Institute (NCI) is also investing more than $425 million a year in hematologic malignancy research. The NCI reported that it earmarked another $81 million in FY2009-2010 in American Recovery and Reinvestment Act funds for blood cancer research.

However, Lichtman is concerned that many of the products are variations on a theme—tinkering with existing chemicals rather than finding new targets. He is also concerned that this approach decreases the potential market for a drug and may not provide a good business plan for pharmaceutical companies. The latter concern is mitigated in part by the ability of academic institutions with federal support to bear some of the early investment costs of drug development.

One example is tipifarnib (Zarnestra, Johnson & Johnson), a farnesyltransferase inhibitor being developed for older adults with newly diagnosed AML. “We have great difficulty treating older patients with cancer because they tend to have more resistant cancers, and they cannot tolerate harsh drug regimens for several reasons. Unfortunately, this time of life is when cancer incidence is greatest,” said Lichtman.

Joseph A. Bertino, MD

“At first, tipifarnib didn’t do well because the percentage of remissions was low,” said Joseph A. Bertino, MD, professor of Medicine and Pharmacology, interim director of the Stem Cell Institute of New Jersey and The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey—Robert Wood Johnson Medical School.

However, researchers learned that if the patient had a high RASGRP1 and a low APTX expression, they were most likely to benefit from tipifarnib-based therapies. “This just shows you how important it is to personalize some of the medicines that we are using,” Bertino said.

Lichtman said that the partnership of academia, the federal government, and industry is essential to encourage the development of personalized medicine for these small subsets of patients. Among the research currently under way, investigators are looking at ways to improve responses to stem cell transplantation, cytotoxic drugs such as thalidomide derivatives, as well as products that target various pathways, including tyrosine kinase, Aurora kinase, RAS, CD30, ABL, and JAK.

“There is a lot of research going on, and many drugs are in the pipeline,” Bertino said. “We await the results of phase II and phase III trials, and new drug combinations that include the use of these novel targeted therapies.”

“We are making progress, but we have a long way to go,” said Lichtman.

Therapies Under Development

Leukemia

Research is paying off at least for some patients with leukemia. According to the NCI, mortality rates for the most common hematologic malignancy have decreased slightly over the last 20 years. The use of tyrosine kinase inhibitors (TKIs) has helped to increase five-year survival rates for many patients with CML.

“Nilotinib and dasatinib look like they are causing a higher percentage of complete remissions than imatinib, and the survival looks better, so I think there will be a shift in the use of some of these newer inhibitors instead of imatinib,” Bertino said.

Despite the success of these TKIs, however, some patients either experience treatment failure or develop resistance, and researchers are exploring compounds for patients who run out of treatment options. Ponatinib (Ariad) and bosutinib (Pfizer) may become options for refractory/resistant patients. Currently, there are no approved therapies after second-line treatment with dasatinib or nilotinib.

The phase II PACE (Ponatinib Ph+ ALL and CML Evaluation) trial is investigating use of ponatinib, an oral pan-BCR ABL, third-generation TKI rationally designed to overcome the T315I mutation, for which currently approved TKIs are largely ineffective. PACE enrolled chronic patients with CML, regardless of disease phase, as well as patients with Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL). All patients are represented by one of two categories: patients resistant or intolerant to previous TKI therapy; and patients with the T315I mutation. In patients with chronic-phase (CP) CML, interim data have demonstrated that treatment with ponatinib achieved a 47% major cytogenetic response rate. Robust responses have been observed so far in all patient cohorts.

In another phase I/II study, bosutinib, an oral, Src/ ABL TKI, showed promise in Ph+ leukemia patients who developed resistance or intolerance to imatinib, dasatinib, and/or nilotinib.

Pfizer has submitted new drug applications in both the United States and Europe for bosutinib to treat adult patients with previously treated Ph+ CML. The labeling includes patients who were resistant or intolerant to imatinib, dasatinib, or nilotinib.

Another target that looks promising for patients who have developed resistance to imatinib are the Aurora kinase inhibitors (AKIs), said Lichtman, but they have had a rocky developmental road. Studies of 1 AKI, MK-0457 (tozasertib, Merck, Vertex) were suspended in 2007 after a clinical safety finding of QTc prolongation was observed. Studies are proceeding for patients who were already enrolled in the trials, but researchers are providing additional monitoring for QTc prolongation.

MK-0457 is being studied in phase II trials in patients with treatment-resistant CML or Ph+ ALL. Companies are also looking at the AKIs in combination with other products, such as dasatinib, in the same group of patients. Another phase I trial is looking at patients with advanced leukemias.

“

We are still relying principally on the same two drug types to treat acute myeloid leukemia (AML) that we used 40 years ago… This demonstrates the need for a broad and aggressive research program, new paradigms, and genius to find new therapies for these cancers.”

—Marshall A. Lichtman, MD

Because outcomes are poor for children with ALL that is refractory to treatment or who relapse, several studies are looking at new options. The novel anti-CD22 immunotoxin moxetumomab pasudotox (previously known as CAT-8015 or HA22), was promising in phase I studies of children with relapsed or refractory ALL. One study showed complete remissions in 3 of 12 patients treated.

A study from the Children’s Oncology Group had mixed results for re-induction therapy with epratuzumab in children with relapsed ALL. Although the children with early relapsed CD22-positive B-cell precursor ALL tolerated the two regimens (epratuzumab alone or with chemotherapy), second remission rates were not better than the control group, which consisted of children who received chemotherapy alone. However, among children who sustained a complete remission, those treated with epratuzumab were more likely to become minimal residual disease-negative as compared with those who received chemotherapy alone.

A JAK kinase inhibitor, ruxolitinib (Jakafi, Incyte) is the first drug specifically approved for the treatment of myelofibrosis. The drug is in clinical trials for other indications, including multiple myeloma and certain leukemias.

One compound that Bertino is watching is CPX-351 (Celator Pharmaceuticals), a liposomal formulation of cytarabine and daunorubicin, which in phase IIb trials showed substantial clinical activity in elderly patients experiencing their first relapse of AML.

Lymphoma

Rituximab (Rituxan, Genentech), the first monoclonal antibody approved for use in cancers, gave the same type of momentum to lymphoma research that imatinib gave to leukemias.

In 2006, the FDA approved an indication for the first-line treatment of patients with diffuse large B-cell, CD20-positive, non-Hodgkin lymphoma (NHL) to be used in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or other anthracycline-based chemotherapy regimens. Since then, the indications have expanded to include first-line treatment of patients with low-grade or follicular B-cell, CD20-positive NHL with cyclophosphamide, vincristine, and prednisone (CVP) or following CVP chemotherapy; or for the treatment of previously untreated or treated patients with chronic lymphocytic leukemia (CLL) in combination with fludarabine and cyclophosphamide (FC). Last year, the FDA expanded the indication again for maintenance therapy for patients with previously untreated CD20-positive B-cell NHL who responded to rituximab in combination with chemotherapy.

Lymphoma, which represents about 5% of all US cancers, has seen a nearly 20% increase in incidence in the past 20 years, during which leukemia incidence has declined slightly. However, the mortality rate for lymphoma has decreased by nearly 50%.

“One of the most exciting drugs, brentuximab vedotin, is in Hodgkin disease,” said Bertino. The FDA approved brentuximab (Adcetris, SeattleGenetics) last year for the treatment of HL and systemic anaplastic large cell lymphoma. Brentuximab is an antibody-drug conjugate that combines the monoclonal antibody brentuximab and with relapsed CD30+ cutaneous lymphoproliferative disorders achieved an objective response, including seven complete remissions and four partial remissions. The company is also looking at using brentuximab earlier in poor-risk patients. Bertino called it “a big step forward” that might produce better salvage regimens.

However, the FDA issued a warning earlier this year about several cases of progressive multifocal leukoencephalopathy (PML), a rare but fatal demyelinating disease associated with brentuximab, and added a new black box warning highlighting this risk to the drug label. In addition, the FDA added a contraindication warning against the use of brentuximab in combination with bleomycin because it increased the risk of pulmonary toxicity.

Pfizer is conducting phase II and III trials of inotuzumab, an investigational antibody that targets CD22, an antigen expressed on about 90% of B-cell malignancies. In early trials, the compound has demonstrated efficacy against CD22(+) B-cell NHL. It is also being looked at with rituximab for patients with relapsed/ refractory aggressive NHL who are not candidates for intensive high-dose chemotherapy.

Novartis plans to file an expanded label application for everolimus (Afinitor), an mTOR inhibitor, to treat lymphoma in 2015. Currently, it is indicated for renal cell carcinoma and pancreatic tumors.

Pixantrone (Pixuvri, Cell Therapeutics), the novel aza-anthracenedione, looks promising for NHL, but it is stalled at the FDA. The company recently withdrew its new drug application and said it will resubmit an application later this year. The Oncologic Drugs Advisory Committee panel rejected its previous application.

The EXTEND trial demonstrated that patients with relapsed/refractory aggressive NHL who were treated with pixantrone compared with other chemotherapy agents achieved significantly higher rate of confirmed and unconfirmed complete remission (CR/CRu), significant increases in overall response rate, significantly greater progression-free survival (PFS), and a positive trend in overall survival.

Pharmacyclics is sponsoring trials of the Bruton’s tyrosine kinase (BTK) inhibitor called PCI-32765 that looks promising against mantle cell and chronic lymphocytic leukemia, said Bertino. “This drug has produced complete remissions in these lymphomas.”

BTK mediates B-cell receptor signaling that is important for normal B-cell development. PCI-32765 appears to directly affect CLL cells by inducing programmed cell death, but also blocks the ability of CLL cells to migrate toward and adhere to lymph nodes. In a phase II trial, PCI-32765 was well-tolerated.

Multiple Myeloma

According to the NCI, the overall incidence and mortality rates of multiple myeloma (MM), which is the second most common blood cancer in the United States, have remained fairly stable over two decades. Every year almost 22,000 people are diagnosed with the disease, and a little over 10,000 die. The five-year survival rate is only about 40%.

Bristol-Myers Squibb and Abbott are working on a monoclonal antibody, elotuzumab, for relapsing MM. Interim results from a phase II trial of elotuzumab showed a partial response or better among patients with relapsed MM who received elotuzumab and lenalidomide and low-dose dexamethasone. The median time to PFS was not reached after 4.9 months of follow-up.

Paul G. Richardson, MD

“There remains a need for more effective and tolerable treatment options for patients with relapsed multiple myeloma, as almost all patients eventually relapse and require further therapy,” according to Paul G. Richardson, MD, clinical director of the Jerome Lipper Center for Multiple Myeloma at the Dana-Farber Cancer Institute, Boston, Massachusetts, in a press release about the results.

The next-generation proteasome inhibitor, carfilzomab, is also being developed for patients with relapsed and refractory MM. Onyx Pharmaceuticals reported on three trials of carfilzomab at the recent American Society of Hematology meeting, in which patients had a durable response and appeared to have an acceptable safety profile. Carfilzomab is being looked at in the phase III ASPIRE trial. Patients with relapsed MM who have received 1 to 3 prior therapies are being randomized to lenalidomide and low-dose dexamethasone with or without carfilzomib. The FOCUS trial, another phase III trial, is looking at carfilzomib as single-agent therapy in the same type of patients.