publication date: Jun. 19, 2020

Clinical Roundup

LLS, NCI and Children’s Oncology Group collaborate on global master clinical trial for acute leukemia

NCI, The Leukemia & Lymphoma Society and the Children’s Oncology Group plan to develop a global precision medicine clinical trial for children with acute leukemia.

The new study, called LLS PedAL (Pediatric Acute Leukemia), is a master clinical trial that will test simultaneously multiple targeted therapies for children who experience a relapse of their acute leukemia, experienced by approximately 40% of children with AML, and 20% of children with high-risk acute lymphoblastic leukemia.

The study will take place at more than 200 sites that are part of the NCI-supported COG network of children’s hospitals, including those in the U.S., Australia, New Zealand, and Canada. The LLS PedAL team will also collaborate with other overseas partners in the UK and EU to implement the trial in those regions. Through these established clinical trial infrastructures, nearly every child in these regions who experiences a relapse of acute leukemia will have access to the trial.

LLS PedAL is a key component of The LLS Children’s Initiative, the society’s $100 million multi-year endeavor to attack pediatric blood cancer from every direction: research grants to advance novel treatments for children, enhanced free education and support services for children and their families, and new policy and advocacy efforts.

LLS led the Beat AML Master Clinical Trial, a precision medicine trial for adults with acute myeloid leukemia. The trial tested novel targeted therapies and identified disease subtypes based on specific biomarkers. Then, researchers matched them with treatments best suited for their diagnosis. A similar model will be used in the LLS PedAL trial, which will match children whose acute leukemia has returned with targeted therapies.

Before the LLS PedAL trial can launch, LLS must secure approval from FDA to begin testing therapies in patients. LLS will be responsible for regulatory submissions to the FDA and will be the Investigational New Drug holder. LLS plans to submit its IND application to the FDA later this year.

The NCI Pediatric Central Institutional Review Board will review all protocols for all of the sites in the COG network before the trial begins. The COG Data Safety Monitoring Committee will provide oversight once the trial is underway.

“Many targeted therapies have been approved to treat adults with acute leukemia over the past decade, but few have been sufficiently studied in children to demonstrate their benefit. This study will give us the opportunity to learn what new targeted therapies are effective for children with acute leukemias,” E. Anders Kolb, Nemours Center for Cancer and Blood Disorders, chair of the COG Myeloid Disease Committee, and LLS Pedal co-chair, said in a statement.

The LLS PedAL trial will launch with three novel therapies to treat children with relapsed acute leukemia, with plans to add additional treatments as they become available. The study will ensure that every child with relapsed AML and many with ALL will be screened to identify their disease subtype and matched to the most appropriate treatment. Some of these patients will participate in LLS PedAL substudies, while others will be referred to other treatments, including other open clinical trials based on discussions with their physicians.

The LLS PedAL trial will include a technology platform to enable participating institutions to consolidate, share and analyze data about pediatric blood cancer patients using standardized terminology. The data will help doctors better understand how children will respond to novel therapies, and the underlying causes of resistance or relapse.


Research and framework for genetic testing in prostate cancer supports broader use of panels, testing in early stage disease

New recommendations from a large, multidisciplinary consensus conference published this week in the Journal of Clinical Oncology suggest expanding use of genetic testing to guide treatment for men with prostate cancer, including the use of panel testing and testing patients with early stage disease.

The full consensus statement can be found in the Journal of Clinical of Oncology.

Taken together with research recently presented by Invitae, the publications underscore the utility of increased access to genetic testing for men with prostate cancer across all stages of disease.

Invitae was among the non-voting sponsors of the conference, which gathered more than 100 experts across a number of specialties with the goal of developing recommendations for how clinicians can use genetic testing to help patients benefit from precision medicine approaches to prostate cancer.

“This framework provides a very thoughtful approach to implementing genetic testing for prostate cancer treatment, screening and family testing,” Sarah Nielsen, a medical affairs liaison at Invitae who previously participated in the conference, said in a statement.

“Importantly, the framework recognizes that changes in a number of different genes can increase prostate cancer risk and therefore encourages greater use of panel testing for men with metastatic disease,” Nielsen said. “With new precision therapies linked to specific genetic changes, increased genetic testing can help identify patients who could benefit from these approaches.”

Among the consensus conference recommendations:

  • Larger panels are useful for patients with metastatic disease

  • Large germline panels and somatic testing were recommended for patients with metastatic prostate cancer. Of the approximately 12-17% of men with metastatic prostate cancer who harbor germline variants, the majority are found in DNA damage repair genes such as BRCA1, BRCA2, ATM, CHEK2, PALB2, and the DNA mismatch repair genes. Large panels provided information across these and other genes of significance, information which is increasingly informing options for PARP inhibitors, immune checkpoint inhibitors, platinum chemotherapy, and clinical trials.

  • Genetic information can support early diagnosis and inform disease surveillance

  • Germline test results are increasingly important for early detection, as men with BRCA2 variants exhibit higher rates of prostate cancer, often with a younger age at diagnosis and more clinically significant disease. Among patients with early-stage disease, emerging data suggest that men with germline BRCA2 mutations and possibly ATM mutations have higher rates of upgrading of prostate biopsies while on active surveillance, suggesting the utility of genetic information in shaping surveillance strategies after diagnosis.

  • Importance of using genetic information requires novel strategies to increase access to counseling resources

  • The guidelines recommend broad access to genetic counseling support but shortages of genetic counselors and wait times for traditional genetic counseling workflows will require development of alternate models for timely and responsible delivery of genetic testing for men and their families. The consensus framework provides suggestions for clinicians on how to counsel and provide alternatives to traditional in-person appointments for patients across a number of issues related to testing, including using pretest education materials and the use of telehealth genetic counseling sessions.

A study presented  at the American College of Medical Genetics and Genomics online annual meeting further underscored the frequency of actionable variants expanded testing can help uncover.

The study of 2,252 men who participated in Invitae’s Detect Prostate Cancer program found an overall positive rate of 13% with no statistical differences in rates among stages of disease. Only half of patients with an actionable variant reported a family history suggestive of increased risk. Nearly three-quarters (71%) of positive patients were eligible for management guidelines and/or potentially eligible for approved precision therapies or clinical trials. These data suggest that broader testing criteria and greater access to testing leads to better informed care for patients and their families.

The consensus conference noted the need for additional research into the associations between genetics and prostate cancer in African-American men, who are 1.8 times more likely to be diagnosed with and 2.2 times more likely to die from prostate cancer. Importantly, this study included 16% participation among African-Americans, which is greater participation than previous similar studies, aligning to the consensus conference research priorities.


Berzosertib shows promise in first clinical trial

In a phase II clinical trial, patients with high-grade serous ovarian cancer who were treated with berzosertib and chemotherapy lived substantially longer than did those treated with chemotherapy alone.

Researchers at Dana-Farber Cancer Institute are conducting the study. The findings were published in The Lancet Oncology.

“Our results in this phase II trial suggest that ATR inhibition in combination with chemotherapy has the potential to offer significant benefit to patients with chemotherapy-resistant HGSOC and, potentially, other tumor types where ATR plays a key role,” lead author Panagiotis Konstantinopoulos, director of translational research, Gynecologic Oncology, at Dana-Farber, said in a statement.

In the study, investigators at 11 cancer centers around the country enrolled 70 patients with HGSOC that was resistant to platinum-based chemotherapy.  Half the participants were randomly assigned to receive the standard chemotherapy agent gemcitabine alone and half received gemcitabine in combination with berzosertib.

“The unbridled growth of cancer cells places enormous stress on the process of DNA replication,” Konstantinopoulos said.  “ATR helps them survive that stress: its job is to coordinate the halting of the cell cycle to check if the DNA is intact or needs repair.  Drugs that inhibit ATR – that deprive tumor cells of such repair – have the potential to be particularly effective in some cancers.”

The estimated median progression-free survival of patients receiving gemcitabine alone – the period in which their disease was in retreat or stable—was 14.7 weeks.  For those receiving gemcitabine and berzosertib, it was 22.9 weeks. Among patients with the most platinum resistant tumors (i.e. those who had progressed within 3 months from prior platinum-based chemotherapy), the difference was even greater: 9 weeks for gemcitabine versus 27.7 weeks for gemcitabine and berzosertib.


Tecentriq improves response rate in early TNBC

The phase III IMpassion031 study, evaluating Tecentriq (atezolizumab) in combination with chemotherapy (Abraxane [albumin-bound paclitaxel, nab-paclitaxel]; followed by doxorubicin and cyclophosphamide) in comparison to placebo plus chemotherapy (including Abraxane), met its primary endpoint by demonstrating a statistically significant and clinically meaningful improvement in pathological complete response for the treatment of people with early triple-negative breast cancer, regardless of PD-L1 expression.

Tecentriq is sponsored by Genentech, a member of the Roche Group.

In the study, fewer patients who received the Tecentriq combination as a neoadjuvant (before surgery) treatment had evidence of tumor tissue detectable at the time of surgery, regardless of PD-L1 expression, in comparison to the control arm.

Safety for the Tecentriq combination appeared to be consistent with the known safety profiles of the individual medicines and no new safety signals were identified.

The IMpassion031 study is the second positive phase III study from Genentech demonstrating the benefit of Tecentriq in TNBC, and the first Tecentriq study to demonstrate benefit in early TNBC. Tecentriq in combination with nab-paclitaxel is approved in more than 70 countries, including the U.S. and across Europe, for the treatment of adults with unresectable locally advanced or metastatic TNBC in people whose tumors express PD-L1 (IC≥1%).


ACE-CL-001, ASCEND trials demonstrate long-term efficacy and tolerability of Calquence in CLL

In the ACE-CL-001 trial, data showed 97% of previously untreated CLL patients continued to respond to treatment after more than four years with no new safety signals.

In the pivotal ASCEND trial, an estimated 82% of CLL patients with relapsed or refractory disease treated with Calquence remained progression free at 18 months vs. 48% for comparators. Overall, Calquence data delivered meaningful long-term clinical benefit with a favorable safety profile for patients with CLL, regardless of whether they’re new to treatment or are managing relapsed or refractory disease.

A link to the ACE-CL-001 trial abstract can be found here, and the ASCEND trial abstract here.


Blood test to monitor cancer is up to 10 times more sensitive than current methods

A method of analysing cancer patients’ blood for evidence of the disease could be up to 10 times more sensitive than previous methods, according to research funded by Cancer Research UK and published in Science Translational Medicine.

The technique uses personalized genetic testing of a patient’s tumour to search blood samples for hundreds of different genetic mutations in circulating tumour DNA. The researchers and their collaborators studied samples from 105 cancer patients, testing the method on small sets of patients with five different cancer types, with both early and late stage disease.

The method detected ctDNA at high sensitivity in patients with advanced breast and melanoma cancer, and in patients with glioblastoma, which is notoriously difficult to detect in blood. The test was also able to detect ctDNA in patients with earlier-stage disease, where the level of ctDNA in the blood is much lower and difficult to find. This included patients with lung or breast cancer, as well as patients with early-stage melanoma who had already had surgery, which makes detection even more difficult.

In the coming years, this method and others based on this approach could lead to tests that more accurately determine if a patient is likely to relapse after having treatment, and could pave the way for the development of pinprick home blood tests to monitor patients.

Combined with new methods to analyze this data to remove background noise and enhance the signal, the team were able to reach a level of sensitivity that in some cases could find one mutant DNA molecule amongst a million pieces of DNA—approximately ten times more sensitive than previous methods.

“Personalised tests that can detect if cancer is still present, or find it early if it is returning, are now being tested in clinical trials,” Nitzan Rosenfeld, senior group leader at the Cancer Research UK Cambridge Institute who led the team at the University of Cambridge that conducted this research, said in a statement.

“Whilst this may be several years away from clinical use, our research shows what is possible when we push such approaches to an extreme. It demonstrates that the levels of sensitivity we’ve come to accept in recent years in relation to testing for ctDNA can be dramatically improved. At present this is still experimental, but technology is advancing rapidly, and in the near future tests with such sensitivity could make a real difference to patients,” Rosenfeld said.

Liquid biopsies to monitor cancer can become much more sensitive. Until recently, personalized liquid biopsies have searched for around 10-20 mutations in the blood and up to around 100 at most. In the material from a tube of blood, these would be able to detect ctDNA to levels on the range of 1 mutant molecule amongst 30,000 pieces of DNA.

This new technique looks for hundreds and sometimes thousands of mutations in each blood sample, routinely achieving a sensitivity of one mutant molecule per 100,000, and under optimal conditions can reach a level measured in parts per million.

In ongoing studies funded by Cancer Research UK, the team and their collaborators plan to use this method to measure ctDNA levels in individuals who are at high risk of developing cancer to help refine future tests for cancer early detection.

Copyright (c) 2020 The Cancer Letter Inc.