publication date: Feb. 1, 2019

Clinical Roundup

Study incorporates patient feedback into better cancer treatments

A study now underway aims to better incorporate patient feedback into clinical trials that help determine which new cancer treatments will be approved for use.

The project, supported by a five-year, $3.4 million grant from NCI, involves statisticians, clinicians and patient advocates. The team is analyzing data from previous and ongoing clinical trials to design new statistical measurement criteria for assessing how well trial participants tolerate experimental therapies.

“There is a pressing need to include the patient’s voice in the evaluation of the toxicity and tolerability of new cancer treatments,” said André Rogatko, director of the Biostatistics and Bioinformatics Research Center at Cedars-Sinai Cancer. “As a consequence of our work, we expect that the future reporting of results from cancer treatment trials can include better evaluations.”

Rogatko is co-leading the study along with Patricia Ganz, professor of Medicine in the David Geffen School of Medicine at UCLA.

New experimental cancer treatments are raising hopes among clinicians and patients for longer survival times and cures. But clinical trials that test such treatments also need to analyze the impact on patients of potentially harsh side effects, known as adverse events, Rogatko said. These side effects may include pain, fatigue, nausea, heart palpitations, skin reactions, mood changes, memory impairment and sexual dysfunction, among others.

“A big unknown is how adverse events affect patients over longer periods of time, particularly in immunotherapy, in which we only recently are learning about long-term toxicity and how it affects quality of life,” Rogatko said.

“As we continue to improve immunotherapy and now combine it with other therapies to make it more effective, we will have to carefully study side effects so that we design combinations that are both more effective and less toxic. That would be a real advance, and this work will help with reaching this goal,” said Dan Theodorescu, director of Cedars-Sinai Cancer.

In recent years, federal agencies have stressed the importance of increased data collection and scrutiny of adverse events experienced by patients while undergoing cancer treatments. The new study aims to advance that effort.

One goal of the study is to use existing and new methods for describing toxicity to show and foretell adverse events. The second goal is to predict the toxicity in a given clinical trial and whether a patient will complete the treatment.

Investigators are using a toxicity index previously developed by Rogatko plus PRO-CTCAE, a set of patient-reported outcome measures designed by the National Cancer Institute to evaluate symptomatic toxicity in patients in cancer clinical trials. The study takes advantage of data from three ongoing immunotherapy trials and three completed National Surgical Adjuvant Breast and Bowel Project trials.

Although the study’s research methods involve highly technical statistical analysis, the emphasis is on improving quality of life for cancer patients, Rogatko said. “We have a chance to give patients more power in how they want to be treated.”

Funding: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number U01CA232859. The grant was awarded in September, and the study will conclude in August 2023.


Patients getting placebo allowed to cross to Erleada as TITAN results unblinded

The Janssen Pharmaceutical Companies of Johnson & Johnson announced unblinding of the phase III TITAN study evaluating Erleada (apalutamide) plus androgen deprivation therapy in the treatment of patients with metastatic castration-sensitive prostate cancer.

The decision resulted from an Independent Data Monitoring Committee recommendation coinciding with a pre-planned analysis that showed the dual primary endpoints were both achieved, significantly improving radiographic progression-free survival and overall survival.

Based on these results, the IDMC recommended that patients in the placebo plus ADT group be given the opportunity to cross over to treatment with Erleada plus ADT. Patients will continue to be followed for OS and long-term safety as part of the TITAN study.

“The TITAN study was designed to evaluate the efficacy and safety of Erleada in combination with androgen deprivation therapy in patients with newly-diagnosed metastatic castration-sensitive prostate cancer, regardless of the extent of their disease,” said Margaret Yu, vice president, Oncology Clinical Development, Janssen Research & Development.

Results from the TITAN study will be submitted for presentation at an upcoming medical congress. Applications seeking regulatory approval of Erleada supported by data from the phase III TITAN study are planned for 2019, the company said.

TITAN is a phase III randomized, placebo-controlled, double-blind study in men who were newly diagnosed with metastatic disease, regardless of prognostic risk, volume of disease, prior treatment with docetaxel or treatment of localized disease.

More than 1,050 patients with mCSPC were randomized to receive either Erleada plus ADT, or placebo plus ADT. Participants were treated until disease progression or the occurrence of unacceptable treatment related toxicity, or end of treatment.

The dual primary endpoints of the study are rPFS and OS.4 Secondary endpoints of the study include time to chemotherapy, time to pain progression, time to chronic opioid use and time to skeletal related event. For additional study information, visit

Erleada (apalutamide) is an androgen receptor inhibitor indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer. It became the first treatment to receive FDA approval for this disease state on Feb. 14, 2018.

The NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer include apalutamide as a treatment option for patients with non-metastatic CRPC with a category 1 recommendation (especially for those with a PSA doubling time ≤10 months)*.

Additionally, the American Urological Association Guidelines for Castration-Resistant Prostate Cancer were updated to include apalutamide with continued ADT as a treatment option that clinicians should offer to patients with asymptomatic nmCRPC. It is included as one of the options clinicians should offer to patients with nmCRPC who are at high-risk for developing metastatic disease (Standard; Evidence Level Grade A).


Antioxidants may enhance chemotherapy treatment for brain tumor

Findings from a pilot study at the University of Missouri School of Medicine show antioxidants such as alpha-lipoic acid may show promise working in tandem with temozolomide to further slow brain tumor growth in glioblastoma.

“Temozolomide is the most common first-line chemotherapy agent for patients with glioblastoma,” said Scott Litofsky, professor and chief of neurological surgery at the MU School of Medicine. “Before temozolomide was available, the median survival for glioblastoma was about nine months. With temozolomide, survival increased to about 14 months. Many patients also take over-the-counter supplements in addition to their temozolomide treatment. We wanted to know whether these supplements assist or hinder chemotherapy treatments.”

Litofsky’s research team studied one glioblastoma cell line taken from consenting patients and another purchased from American Tissue Culture Collection. The researchers pre-treated the glioblastoma cell lines with varying concentrations of one of three anti-oxidants—vitamin D3, melatonin or alpha-lipoic acid—for 72 hours followed by a 72-hour treatment with temozolomide.

The researchers found using the antioxidants in combination with the drug slowed cancer cell growth at varying levels. Specifically:

  • Vitamin D3 alone did not affect the glioblastoma cells but did have a slight benefit when offered in combination with temozolomide.

  • Melatonin alone decreased cancer cell growth in the pre-treatment phase by more than 60 percent, but showed no significant slowing of cell growth in combination with chemotherapy treatment.

  • Alpha-lipoic acid reduced cell growth by more than 50 percent in both the pre-treatment and chemotherapy phase compared to the control in one cell line, and 44 percent in the other.

  • Both melatonin and alpha-lipoic acid significantly enhanced the effectiveness of temozolomide’s ability to destroy cancer cells.

“The dose of alpha-lipoic acid that we used in our cell cultures is a dose that can be attainable when a person takes the antioxdant orally,” said Dianne McConnell,senior research specialist in the Division of Neurological Surgery at the MU School of Medicine. “Alpha-lipoic acid showed in our study that it may affect the cells that escape treatment with chemotherapy. If the alpha-lipoic acid can decrease the growth of those cells by the time they do the next dose of chemotherapy, the tumor can’t grow, and chemotherapy might be more effective.”

Although these results show promise, more studies are necessary before determining the effectiveness of combining antioxidants with temozolomide to treat glioblastoma in humans. The researchers’ next step is to test alpha-lipoic acid in tandem with temozolomide in mice.

In addition to Litofsky and McConnell, the study authors include Joe McGreevy, University of Missouri School of Medicine, and Macy Williams, undergraduate student, University of Missouri.

Their study, “Do Antioxidants Vitamin D3, Melatonin, and Alpha-Lipoic Acid Have Synergistic Effects with Temozolomide on Cultured Glioblastoma Cells?” was recently published by the journal Medicines.

Research reported in this publication was supported by Head for the Cure Foundation and Stand Up to Cancer.

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