Phase 2 Basket Trial for Relapsed/ Refractory Osteosarcoma

Osteosarcoma is the most common form of primary bone cancer and it affects primarily children, adolescents and young adults. While a significant percentage of patients with localized, appendicular disease who respond well to chemotherapy survive, the prognosis for patients who do not respond to chemotherapy, or are metastatic, or have an axial primary tumor is poor. In addition, about half of all
patients will relapse and long-term survival after relapse is very poor. The current treatments have not changed or improved survival in over 30 years, and a new approach to treatment is desperately needed.

Osteosarcoma is notable for its disordered and highly heterogeneous genome. Recent studies indicate that TP53 has been knocked out in at least 90% and possibly 100% of all osteosarcomas. Using a dataset of 171 tumors which underwent next generation sequencing, Beech did a regression analysis which identified seven distinct genotypes, and further analysis has identified trends between certain
genotypes and prognosis, as well as response to therapy (e.g. RB1 deleted/mutated tumors have the best response to chemotherapy).

MYC amplification appears in about one quarter of all tumors. These patients have a disease which is highly aggressive, relapses quickly and widely (or may never become NED), and is extremely resistant to current treatments. The poor outcomes appear to be independent of whether or not the disease is initially localized or metastatic, where the primary tumor is located, and what the response to
chemotherapy is. As in neuroblastoma, MYC amplification is mutually exclusive of ATRX deletion. There are several experimental therapies in clinical trials which target MYC directly or indirectly.

Disruptions in the mTOR pathway are also common (PTEN deletions, AKT1/2 amplifications, TSC1/2 mutations) (10-25%). There are several approved therapies for the mTOR pathway. CDK4 amplification occurs in about 15% of tumors. Palbociclib is an approved CDK4/6 targeted therapy. There are additional genetic targets available in osteosarcoma.

Phase 2, single agent trials of osteosarcoma have been uniformly unsuccessful. A recent soft tissue sarcoma trial combining Olaratumab and Doxorubicin showed a very significant progression-free and overall survival benefit in inoperable, metastatic patients. We are proposing a Phase 2 Basket Trial which will combine a targeted therapy based on tumor genetics with chemotherapy. We will genetically sequence relapsed/refractory osteosarcoma tumors and assign patients to one of several cohorts depending upon the tumor genetics. The exact cohorts and combinations of drugs to be used are still under design.

This trial will be the first step in a precision medicine approach to osteosarcoma. It will also be the first time that tumor genetics is systematically used to treat the disease, and it will be the first time that research by a pediatric cancer parent is being used as part of the justification for an osteosarcoma clinical trial. If successful, this trial will represent a breakthrough in osteosarcoma treatments, and will also help provide a roadmap for the application of precision medicine to other difficult to treat pediatric sarcomas.