A phase II study of temsirolimus and liposomal doxorubicin for patients with recurrent and refractory bone and soft tissue sarcomas

Background

Relapsed and refractory sarcomas continue to have poor survival rates. The cancer stem cell (CSC) theory provides a tractable explanation for the observation that recurrences occur despite dramatic responses to upfront chemotherapy. Preclinical studies demonstrated that inhibition of the mechanistic target of rapamycin (mTOR) sensitizes the CSC population to chemotherapy.

Methods

Here we present the results of the Phase II portion of a Phase I/II clinical trial that aimed to overcome the chemoresistance of sarcoma CSC by combining the mTOR inhibitor temsirolimus (20 mg/m² weekly) with the chemotherapeutic agent liposomal doxorubicin (30 mg/m² monthly).

Results

Fifteen patients with relapsed/refractory sarcoma were evaluable at this recommended Phase 2 dose level. The median progression free survival was 315 days (range 27–799). Response rate, defined as stable disease or better for 60 days, was 53%. Nine of the patients had been previously treated with doxorubicin. Therapy was well tolerated. In a small number of patients, pre- and post- treatment tumor biopsies were available for assessment of ALDH expression as a marker of CSCs and showed a correlation between response and decreased ALDH expression. We also found a correlation between biopsy-proven inhibition of mTOR and response.

Conclusions

Our study adds to the literature supporting the addition of mTOR inhibition to chemotherapy agents for the treatment of sarcomas, and proposes that a mechanism by which mTOR inhibition enhances the efficacy of chemotherapy may be through sensitizing the chemoresistant CSC population. Further study, ideally with pre- and post-therapy assessment of ALDH expression in tumor cells, is warranted.Trial registration The trial was registered on clinicaltrials.gov (NCT00949325) on 30 July 2009. http://www.editorialmanager.com/csrj/default.aspx

     

Immune checkpoint inhibitors: The linchpins of modern immunotherapy

Immune checkpoint inhibitors (ICIs) have revolutionized our approach to cancer treatment in the past decade. While monoclonal antibodies to CTLA‐4 and PD‐1/PD‐L1 have produced remarkable and durable responses in a subset of patients, the majority of patients will still develop primary or adaptive resistance. With complex mechanisms of resistance limiting the efficacy of checkpoint inhibitor monotherapy, it is critical to develop combination approaches to allow more patients to benefit from immunotherapy. In this review, I approach the current landscape of ICI research from the perspective of sarcomas, a rare group of bone and soft tissue cancers that have had limited benefit from checkpoint inhibitor monotherapy, and little investigation of biomarkers to predict responses. By surveying the various mechanisms of resistance and treatment modalities being explored in other solid tumors, I outline how ICIs will undoubtedly serve as the critical foundation for future directions in modern immunotherapy.     

Malignant progression of a peripheral nerve sheath tumor in the setting of rhabdoid tumor predisposition syndrome

Malignant progression of a benign or low‐grade tumor in individuals with germline alteration of SMARCB1 gene is not well characterized. In a family in which two carrier children had germline SMARCB1 mutations and atypical teratoid rhabdoid tumor, we report malignant progression of a nerve sheath tumor over a 7‐year period in an affected adult family member. Prompt identification of the germline SMARCB1 alteration and the resultant rhabdoid tumor predisposition syndrome can help guide genetic counseling and surveillance in affected family members.     

A phase I trial of vertical inhibition of IGF signalling using cixutumumab,an anti-IGF-1R antibody,and selumetinib,an MEK 1/2 inhibitor,in advanced solid tumours

Background:

We completed a phase I clinical trial to test the safety and toxicity of combined treatment with cixutumumab (anti-IGF-1R antibody) and selumetinib (MEK 1/2 inhibitor).

Methods:

Patients with advanced solid tumours, refractory to standard therapy received selumetinib hydrogen sulphate capsules orally twice daily, and cixutumumab intravenously on days 1 and 15 of each 28-day cycle. The study used a 3+3 design, with a dose-finding cohort followed by an expansion cohort at the maximally tolerated dose that included pharmacokinetic and pharmacodynamic correlative studies.

Results:

Thirty patients were enrolled, with 16 in the dose-finding cohort and 14 in the expansion cohort. Grade 3 or greater toxicities included nausea and vomiting, anaemia, CVA, hypertension, hyperglycaemia, and ophthalmic symptoms. The maximally tolerated combination dose was 50 mg twice daily of selumetinib and 12 mg kg⁻¹ every 2 weeks of cixutumumab. Two patients achieved a partial response (one unconfirmed), including a patient with BRAF wild-type thyroid carcinoma, and a patient with squamous cell carcinoma of the tongue, and six patients achieved time to progression of >6 months, including patients with thyroid carcinoma, colorectal carcinoma, and basal cell carcinoma. Comparison of pre- and on-treatment biopsies showed significant suppression of pERK and pS6 activity with treatment.

Conclusions:

Our study of anti-IGF-1R antibody cixutumumab and MEK 1/2 inhibitor selumetinib showed that the combination is safe and well-tolerated at these doses, with preliminary evidence of clinical benefit and pharmacodynamic evidence of target inhibition.     

Extrathoracic Location and “Borderline” Histology are Associated with Recurrence of Solitary Fibrous Tumors After Surgical Resection

Background

Most solitary fibrous tumors (SFTs) are cured by complete resection, but many recurrent and metastatic SFTs do not respond to treatment and are fatal. Malignant histology, defined by England’s pathologic criteria, is strongly associated with recurrence, but some benign SFTs still behave aggressively. Several studies have suggested that extrathoracic SFTs have a worse prognosis. We reviewed thoracic and extrathoracic SFTs from our institution to determine if extrathoracic location is associated with recurrence, independent of malignant histology.

Methods

With IRB approval, we retrieved patient pathology reports from the Johns Hopkins Surgical Pathology database between 1991 and 2011 and included 83 SFT patients in our analysis. Patient history and outcomes were obtained from the medical record and primary care physicians. Predictors of recurrence were analyzed by univariate and multivariate analysis and survival determined by the Kaplan–Meier method.

Results

Of the 83 patients, 59 had extrathoracic SFTs in neurologic (n = 24), extremity or head/neck (n = 13), or visceral/intraabdominal (n = 22) sites. A total of 74 SFTs were classified benign and 9 as malignant. Of the 14 recurrences, 13 occurred in extrathoracic SFTs; only 7 were classified as malignant. Multivariate analysis confirmed that malignant histology had the strongest association with recurrence, but extrathoracic location also independently predicted recurrence. A total of 20 benign SFTs possessed 1 or more of England’s criteria but to an insufficient degree for malignant classification. These “borderline” SFTs were more likely to recur than benign SFTs without these features.

Conclusions

Extrathoracic and “borderline” SFTs with any of England’s criteria have a higher risk of recurrence.     

A dose‐finding study of temsirolimus and liposomal doxorubicin for patients with recurrent and refractory bone and soft tissue sarcoma

There are few effective therapies for high‐risk sarcomas. Initial chemosensitivity is often followed by relapse. In vitro, mammalian target of rapamycin (mTOR) inhibition potentiates the efficacy of chemotherapy on resistant sarcoma cells. Although sarcoma trials using mTOR inhibitors have been disappointing, these drugs were used as maintenance. We conducted a Phase I/II clinical trial to test the ability of temsirolimus to potentiate the cytotoxic effect of liposomal doxorubicin and present here the dose‐finding portion of this study. Adult and pediatric patients with recurrent or refractory sarcomas were treated with increasing doses of liposomal doxorubicin and temsirolimus using a continual reassessment method for escalation, targeting a dose‐limiting toxicity rate of 20%. Blood samples were drawn before and after the first dose of temsirolimus in Cycles 1 and 2 for pharmacokinetic analysis. The maximally tolerated dose combination was liposomal doxorubicin 30 mg/m² monthly with temsirolimus 20 mg/m² weekly. Hematologic toxicity was common but manageable. Dose‐limiting toxicities were primarily renal. Concurrent administration of liposomal doxorubicin resulted in increased exposure to sirolimus, the active metabolite of temsirolimus. Thus, the combination of liposomal doxorubicin and temsirolimus is safe for heavily pretreated sarcoma patients. Co‐administration with liposomal doxorubicin did not alter temsirolimus pharmacokinetics, but increased exposure to its active metabolite.     

Growing Pains: a Simulation-Based Curriculum for Improving the Transition to Hematology/Oncology Fellowship

Trainee exposure to clinical oncology during residency training is heterogeneous and often modest. The steep learning curve upon entry into fellowship can result in undue stress for fellows and their patients. Simulation-based training has been shown to be superior to classical didactic approaches. We have introduced several innovative simulation-based workshops into the curriculum for the Johns Hopkins Hematology/Oncology Fellowship Training Program in order to address this unmet need. During the first months of training, fellows were engaged in activities emphasizing essential clinical and procedural skills. Specific workshops included the following: (1) chemotherapy writing, (2) cadaveric and simulation-based bone marrow biopsy and intrathecal chemotherapy administration, and (3) simulation-based communication skills training. All first-year fellows in our program participated in these exercises. Pre- and post-workshop surveys were administered to assess knowledge, attitudes, and behaviors; additional distant post-workshop evaluations were disseminated to assess the durability/impact of the curricula and for program evaluation. Overall, participating fellows indicated that the workshops improved patient care and comfort with procedures and patient-centered communication. Continued implementation of these workshops was recommended for program improvement. To the best of our knowledge, ours is amongst the first oncology fellowship training programs to systematically implement simulation-based curricula into our schema for fellowship training. We hypothesize that proactively introducing fellows to these high-yield activities will translate into improved patient care and reduced stress for trainees. Additional investigation into the long-term impact of such curricula remains an area of ongoing need.