Therapies for patients with rare tumors and genetic tumor predisposition

Division Of Clinical Sciences - Nci

Investigators

Linked publications & trials

Abstract

Aim 1: Natural history and clinical trials for NF1 related peripheral nerve sheath tumors: People with NF1 develop multiple tumors including cutaneous neurofibromas (cNF), which never transform to malignancy; plexiform neurofibromas (PN), which are histologically benign but can cause substantial morbidity and transform to highly aggressive cancers called malignant peripheral nerve sheath tumors (MPNST); atypical neurofibromas (AN), which are histologically borderline lesions and at risk for transformation to MPNST. Our NIH NF1 natural history study allowed us to comprehensively characterize the growth rate of PN in NF1 and the development of associated morbidities. In our study the majority of PN were associated with morbidities (for example, pain, disfigurement, airway or motor dysfunction), which manifest at an early age. Using volumetric MRI analysis of PN to longitudinally monitor PN growth we identified that PN grow most rapidly in young children compared to adults who typically have minimal or no growth of their PN. My team directed a series of clinical trials targeting NF1 PN with the goal of the progression free survival (PFS) or achieving PN volume reduction. With the exception of pegylated interferon alpha-2b, none of the trials resulted in a partial response (PR), defined as PN volume reduction greater or equal to 20% compared to baseline, or clinically meaningful improvement in PFS. We then identified the MEK inhibitor selumetinib as the first active agent against NF1 PN. In a phase I clinical trial for children with inoperable PN we reported PN shrinkage in 71% of patients. Subsequently we developed a phase II clinical trial which incorporated standardized patient reported and functional outcome measures in addition to assessment of response by volumetric MRI analysis. This larger phase II trial confirmed the previously reported response rate. In addition, we observed clinically meaningful improvement in pain and function and lesser disfigurement. Based on the results of this trial selumetinib received FDA approval for children with NF1 and inoperable, symptomatic PN in April 2020, and has since been approved in more than 30 countries. Dr. Andrea Gross in the POB has developed a trial, which will assess if selumetinib can prevent the development of morbidity in young children with asymptomatic but growing PN. In collaboration with the NCI Adult Developmental Therapeutics Clinic we are currently also conducting a phase II trial of selumetinib for adults with NF1 and inoperable PN. We have been successful at obtaining paired tumor research biopsies on this trial in most patients. The trial recently completed enrollment and the observed activity is similar to children with NF1. We are collaborating with Drs. Drs. Jack Shern and Taylor Sundby in the POB to identify biomarkers of malignant transformation such as cell free DNA and single cell sequencing of resected tumors. We have made substantial progress in the understanding AN. Through comprehensive evaluations we have identified that AN are precursor lesions for MPNST. Our collaborator, Dr. Prashant Chittiboina, neurosurgeon at NINDS, subsequently demonstrated that many AN can be safely removed surgically with marginal margins. Resection of these lesions may thus be a way to prevent malignant transformation. AN are characterized by heterozygous CDKN2A/B loss. We therefore developed a clinical trial of the CDK4/6 inhibitor abemaciclib specifically for patients with NF1and unrespectable AN, which is open for enrollment. Aim 2: Natural history and clinical trials for children and adults with rare tumors: The primary goal is to develop new agents for the treatment of cancers and other rare tumors or genetic tumor predisposition. Clinical trials target refractory solid tumors such as Ewing sarcoma or rhabdomyosarcoma, medullary thyroid carcinoma (MTC), and very rare tumors with no known effective medical therapy such as alveolar soft part sarcoma, or chordoma. We also aim to understand the biology and natural history of these rare tumors through the Cancer Moonshot MyPART network, described in a separate report. Examples of clinical trials ongoing and in development include a phase I and II trial of cabozantinib (XL184) for refractory solid tumors and select solid tumor strata. Cabozantinib is a small molecule inhibitor of multiple receptor tyrosine kinases (RTK) including MET, VEGFR2, RET, KIT and TIE-2, that are overexpressed in a variety of pediatric cancers. We collaborated with the COG PEP-CTN in the development of a cabozantinib in a phase I and II trial. The phase II trial completed enrollment and recently reported activity in patients with refractory osteosarcoma. In collaboration with SARC and Dr. Patrick Grohar (Children's Hospital of Philadelphia, PA) we are conducting a phase I/II clinical trial of trabectedin and irinotecan for patients with Ewing sarcoma. The correlative FLT-PET imaging is performed at the NIH Clinical Center for these patients. We have a substantial effort in the development of effective therapies for MPNST, a highly aggressive sarcoma. Approximately 50% of MPNST occur in people with NF1. In collaboration with Dr. Karen Cichowski (Brigham and Women Hospital Boston, MA), who conducts preclinical trials with targeted therapies in her NF1 transgenic MPNST mouse model, Dr. AeRang Kim (Children's National Hospital, Washington, DC) and the sarcoma cooperative group SARC we have conducted several clinical trials specifically for MPNST, unfortunately not achieving the desired response rates. A new phase I/II clinical trial combining a MEK inhibitor, a bromodomain inhibitor and a PD-L1 inhibitor is in development for patients with refractory sarcomas and MPNST based on data from the Cichowski and DeRaedt lab demonstrating substantial tumor shrinkage in mice and will commence enrollment soon. An example for our collaboration with the NCI DTC to provide access to promising investigational therapies to children and young adults with refractory solid tumors is Dr. Chen's phase II trial of nilotinib and paclitaxel for patients with many rare tumors, which is open for enrollment for patients 12 years and older. We are also collaborating with Dr. Chen by enrolling children with refractory cancers such as alveolar soft part sarcoma, on primarily adult clinical trials directed by her. Similarly, Dr. Chen evaluates adult patients on clinical trials coordinated by the Pediatric Oncology Branch trials. This ensures that children and adults with rare tumors get optimal access to targeted therapies. The NCI POB and my Section have a leadership role in several NCI Initiatives: The NCI CCR Rare Tumors Initiative (RTI) fosters focused collaborations between basic and clinical researchers at NCI (CCR and DCEG), as well as extramural investigators. The Rare Tumor Patient Engagement Network (RTPEN), supported by the Cancer Moonshot, aims to connect patients and investigators through shared infrastructure and networks, accelerate the understanding of rare tumors and develop clinical trials for rare tumors through these national and international collaborations of patients, advocates, clinicians, clinical and basic researchers, and other stakeholders. Given the success of selumetinib in the treatment of the rasopathy NF1, we collaborated with CCR, DCEG and extramural investigators in the development of the Advancing RAS/Rasopathies Therapies (ART) program, which takes a comprehensive approach to study RASopathies.