Clinical trial NCT02584647
Conditions: Sarcoma Malignant Peripheral Nerve Sheath Tumors
Keywords: Unresectable
Sponsor: Gulam Manji
Start date: 2015-11-04; Completion date: 2024-10-01
Enrollment: 39 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if treatment with PLX3397 and Sirolimus will be tolerated and result in shrinking of the cancer or stopping the cancer from growing. In the phase I portion, the maximum tolerate dose of the study drug will be determined. In the Phase II portion, progression free survival will be assessed at the dose level found in Phase I. Participants will continue to take the study drug until they experience an unacceptable side effect or their disease progresses. Funding Source - FDA OOPD

Detailed description:
Malignant peripheral nerve sheath tumors (MPNSTs) represent up to 10% of adult soft tissue sarcomas. Due to its rarity, few MPNST-specific prospective trials exist, and treatments are largely based on extrapolation from results from other sarcoma subtypes. Since the molecular pathways driving pathogenesis within sarcoma subtypes are distinct, these treatment options are likely suboptimal at best. Targeted therapies that block key pathways known to drive MPNST will likely result in superior tumor responses with limited toxicities.

Arms: arm 1: Subjects with unresectable or metastatic sarcoma will take orally PLX3397 (600 - 1000mg) in combination with Sirolimus (2-6mg) daily. arm 2: Subjects with unresectable or metastatic Malignant Peripheral Nerve Sheath Tumors (MPNSTs) will take PLX3397 and Sirolimus at the recommended Phase 2 dose (RP2D).
Interventions: intervention 1: PLX3397 intervention 2: sirolimus
Intervention descriptions: intervention 1: PLX3397 is a small molecule that potently and selectively inhibits macrophage colony-stimulating factor receptor (FMS), Kit, and FMS-like tyrosine kinase 3 (Flt3)-internal tandem duplication (ITD) kinases, which regulate key components of the tumor microenvironment and oncogenic variants of these kinases that drive certain tumors. intervention 2: Sirolimus is a macrocyclic lactone that binds to tacrolimus (FK506) binding protein 12 and inhibits mammalian target of rapamycin (mTOR) resulting in cell-cycle arrest and apoptosis.

Sirolimus is currently approved as an immunosuppressive agent for organ transplantation and more recently, as a component of cardiac arterial stents because of its potent antiproliferative effects on fibroblasts responsible for restenosis after such a procedure (26) Sirolimus is commonly administered orally on a daily basis, in doses ranging from 2 to 40 mg/day.

Protocol documents:
Prot_SAP_000.pdf: 
Phase I Study Evaluating Combination Therapy 
With the Receptor Tyrosine Kinase Inhibitor 
PLX3397 and Sirolimus in Patients With 
Unresectable Sarcoma and Phase II Study in 
Malignant Peripheral Nerve Sheath Tumors  
NCT02584647
Protocol Date: April 21, 2021


Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 04/21/2021 
INTRODUCTION 
Malignant peripheral nerve sheath tumors (MPNST) are soft-tissue tumors with a poor 
prognosis (1). They are highly aggressive and therapeutically resistant tumors that arise in 
connective tissue surrounding peripheral nerves. MPNSTs occur in a subset of patients 
with Neurofibromatosis type 1 (NF1), an autosomal dominant genetic disorder (2, 3). There 
is a 10% chance that patients with NF1 will develop MPNSTs in their lifetime (4, 5). 
Despite advances in cancer treatment, MPNSTs typically remain fatal and there is an unmet 
need to develop new therapeutic strategies in this disease setting. 
Growth factor dependent pathways driven specifically by receptor tyrosine kinases (RTKs) 
have been of particular interest due to their crucial role in tumor progression and survival. 
Targeting single or multiple RTK pathways using small molecule inhibitors is an attractive 
therapeutic treatment option for blocking sarcoma cell growth. Such inhibitors have been 
used in sarcoma patients with some promising results (6, 7). In addition to the RTKs, 
mTOR (mammalian target of Rapamycin) protein plays a key role in AKT activation and 
downstream survival signaling. Blocking RTK signaling pathways such as c-Kit and 
PDGFR using multi-targeted inhibitors like Imatinib mesylate (Imatinib) has been used 
with some encouraging results in in vitro models of MPNSTs (8-10). However, MPNSTs 
still remain one of the most challenging sarcoma subtypes to treat and novel therapeutic 
approaches are urgently needed to treat this disease. 
MPNSTs have been shown to have gene amplification for receptor tyrosine kinases such 
as PDGFR as well as c-Kit (9, 11). The role of c-Kit oncogenic mutations in gastro-
intestinal stromal tumors (GIST) is well established (12, 13). MPNSTs contain PDGFR 
and c-Kit gene amplifications and mutations within PDGFR have been identified (9). 
Imatinib, an inhibitor of c-Kit and PDGFR, which is approved for the treatment of GIST, 
has been shown to be active in patients with plexiform neurofibromas, a slow growing, 
chemotherapy resistant tumor that develops in patients with NF (14).  However, in clinical 
trials, response rates to imatinib in neurofibromatosis are only in the order of 17%, 
indicating that alternate signaling pathways must be involved in the growth and 
development of tumors associated with NF1 loss (14).  Though imatinib has never been 
formally tested in MPNST, it has been evaluated in patients affected by NF1 loss who 
developed GIST.  Similar to MPNST patients, the overall prognosis of this patient 
population is poor, and the response to imatinib in NF1-associated GIST is very low (15).  
In a recently reported study, Pexidartinib, also referred to as Turalio®, a tyrosine kinase 
inhibitor that selectively targets c-FMS and c-KIT receptors, resulted in superior target 
inhibition and tumor growth suppression when compared to imatinb in in vitro and in vivo 
models of MPNST (16). Recently it has also been reported that macrophage infiltration of 
both mouse and human neurofibromas correlates with disease progression. Macrophages 
account for almost half of neurofibroma cells. In the Dhh-Cre/Nf1 mouse model of 
neurofibroma, Turalio® has been shown to cause neurofibroma regressions and to block 
macrophage infiltration (17). Moreover, addition of TORC1 inhibitor rapamycin to 
Turalio® resulted in sustained tumor suppression by decreased cell proliferation and 
macrophage tumor depletion, a marker thought to be critical for tumor progression (18). 


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These significant pre-clincal findings are the basis of the proposed phase I/II study in 
patients suffering from MPNST, a disease whose treatment options are limited. 
1.
STUDY OBJECTIVES
1.1 
Primary Objective 
Phase 1 study: 
a. To determine the recommended phase 2 dose (RP2D) for Turalio® when administered
orally in combination with Sirolimus in patients with unresectable or metastatic sarcoma.
b. To evaluate the safety profile of Turalio® with Sirolimus in patients with unresectable
or metastatic sarcoma.
Phase 2 study: 
a. To determine the preliminary efficacy of Turalio® in combination with Sirolimus in
patients with unresectable or metastatic MPNST by determining the median progression
free survival.
b. To evaluate the safety profile of Turalio® with Sirolimus at the RP2D in patients with
unresectable or metastatic MPNST.
1.2 
Secondary Objective 
To investigate the objective response rate (ORR) and overall survival (OS) of patients with 
unresectable malignant peripheral nerve sheath tumors (MPNSTs). Response rate endpoint 
will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. 
1.3 
Exploratory Objective 
a. Analysis of TORC1/TORC2 signaling pathways and receptor tyrosine kinase activity
including c-FMS, c-KIT, AKT, S6, and assessment of macrophage activation.
2.
BACKGROUND
Malignant peripheral nerve sheath tumors (MPNSTs) represent up to 10% of adult soft 
tissue sarcomas. Due to its rarity, few MPNST-specific prospective trials exist, and 
treatments are largely based on extrapolation from results from other sarcoma subtypes. 
Since the molecular pathways driving pathogenesis within sarcoma subtypes are distinct, 
these treatment options are likely suboptimal at best. Targeted therapies that block key 
pathways known to drive MPNST will likely result in superior tumor responses with 
limited toxicities. 
Growth factor-dependent pathways driven by receptor tyrosine kinases (RTKs) play a 
crucial role in tumor progression and survival.  Targeting RTKs to abrogate sarcoma 
growth remains an attractive proposition, but the challenge of pursuing the correct 
combination of pathways remains unsolved.  mTOR activation is critical for sarcoma 
growth but monotherapy has shown little clinical benefit. Advanced sarcoma patients with 
stable disease when treated with Ridaforolimus, an mTOR inhibitor, resulted in a tumor 
response of 1.3% (19). This may in part be due to the release of a negative feedback 


Columbia University Medical Center 
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mechanism identified in several cancers by activation of AKT through RTKs (20). We 
have reported that this survival mechanism is mediated predominantly through both IGF-
1R and PDGFR signaling and that dual inhibition of mTOR and RTKs (including IGF-1R 
or PDGFR) result in a greater degree of growth inhibition compared to inhibition of either 
pathway alone (21). We showed that this relationship between mTOR targeting and AKT 
activation was most striking in synovial cell sarcoma cells where PDGFRα is highly 
expressed.  This would suggest that the interaction between mTOR and AKT is intricately 
context dependent and based on the RTK expressed by the sarcoma cell. The overall 
desired effect with these combinations is to inhibit both mTOR and pAKT by targeting the 
RTK that is activated upon mTOR inhibition. Multiple signaling pathways play a role in 
MPNST growth, and include c-KIT, PDGFR, mTOR, and c-FMS. c-FMS, a RTK involved 
in macrophage activation and tumor infiltration has also been shown to play a role in tumor 
growth and maintenance (22). It is likely that these pathways are not mutually exclusive 
and function in concert to propagate cancer growth in MPNSTs. Thus developing ways to 
block these multiple pathways could result in an improved therapeutic effect. 
Release of negative feedback mechanism by mTOR 
inhibition is blocked by Turalio® . To identify sarcoma 
subtypes that may be susceptible to Turalio®, our group 
screened multiple cell lines for c-FMS and c-KIT 
expression. Only cell lines from MPNST and GIST 
expressed c-KIT. Turalio® showed activity in in vitro 
cell viability assays in GIST and MPNST cell lines and 
blocked c-KIT and AKT phosphorylation in a dose 
dependent manner (18). MPNST cells treated with 
Sirolimus blocked p-S6, but resulted in increased p-KIT, 
p-AKT, and p-PDGFR likely through the release of the
negative feedback mechanism (Fig. 1, 18). Co-treatment 
with Turalio® or imatinib reversed this effect and 
resulted in increased apoptosis, as indicated by PARP cleavage (Fig. 1, 18). In cell viability 
assays, Turalio® and Sirolimus had potent activity compared to either agents alone, or with 
the combination of imatinib and Sirolimus (18). 
Turalio® and Sirolimus suppress tumor growth in an MPNST xenograft model. 
Turalio® in combination with Sirolimus resulted in sustained inhibition of target RTKs as 
well as tumor growth even after treatment was discontinued (Fig. 2, 18). In contrast, 
combination treatment with imatinib was less effective in controlling tumor growth (18). 
Pexidartinib  
Imatinib 
Sirolimus 
cleaved PARP 
p-c-KIT 
p-c-PDGFR 
p-AKT 
p-S6 
Fig.1. Immunoblot analysis on MPNST 
cell lysates treated with PLX, Imatinib  
(imat), and/or sirolimus. 
18     
Pexidartinib  
Imatinib 
Sirolimus 
cleaved PARP 
p-c-KIT 
p-c-PDGFR 
p-AKT 
p-S6 
Fig.1. Immunoblot analysis on MPNST 
cell lysates treated with PLX, Imatinib  
(imat), and/or sirolimus. 
18     
Pexidartinib  
Imatinib 
Sirolimus 
cleaved PARP 
p-c-KIT 
p-c-PDGFR 
p-AKT 
p-S6 
Fig.1. Immunoblot analysis on MPNST 
cell lysates treated with PLX, Imatinib  
(imat), and/or sirolimus. 
18     


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Turalio® and Sirolimus block macrophage tumor infiltration. Macrophage infiltration 
within neurofibromas correlates with disease progression in both animal models and 
humans. In a mouse neurofiborma 
model, Turalio® blocked macrophage 
infiltration and caused neurofibroma 
regressions 
 
(17). 
Macrophage 
infiltration, 
as 
detected 
by 
immunohistochemistry (IHC) using 
Iba-1 specific antibody, in MPNST 
xenografts indicated potent inhibition 
when mice were treated with Turalio® 
and Sirolimus as compared to treatment 
with imatinib and/or Sirolimus (Fig. 
3A). 
Furthermore, 
Turalio® 
and 
Sirolimus 
treatment 
resulted 
in 
sustained inhibition of macrophage 
tumor infiltration even one week after 
treatment was discontinued (Fig. 3B, 18). 
Rationale - MPNSTs are fatal tumors that are resistant to chemotherapy and lack 
treatment options. As mentioned previously, multiple RTK including c-KIT, PDGFR, c-
FMS, and mTOR play a critical role in MPNST pathogenesis and survival. However, 
targeted mono-therapies which include erlotinib, sorafenib, imatinib, and dasatinib have 
failed to yield an appreciable response in this disease (23, 24). Similarly, mTOR 
inhibitors have been ineffective in controlling sarcoma growth in clinical studies (23). In 
order to effectively target 
MPNSTs, both mTOR and the 
RTK that it activates as a result 
of mTOR inhibition, needs to be 
targeted simultaneously to 
maximize antineoplastic activity. 
Since Turalio® does not inhibit 
the mTOR pathway, we added 
Sirolimus and tested the 
combination in in vitro and in 
vivo models of MPNST, as 
previously described. 
Our key pre-clinical results indicate that Turalio® and Sirolimus – 
•
Inhibit MPNST cell viability more potently when compared to imatinib and
Sirolimus.
•
Inhibit c-KIT, PDGFR, AKT, and S6 phosphorylation in vitro in addition to c-
FMS phosphorylation in vivo.
•
Result in sustained tumor growth suppression in an MPNST xenograft model.
Fig. 2. Effect of PLX and sirolimus treatment on MPNST 
xenografts. 
Treatment with 
PLX 
alone, 
or in 
combination with sirolimus was stopped on day 24 as 
depicted by the arrow. 
18 
Tumor  
Vol 
(mm
3) 
Time (Days)   
Fig. 3. PLX and sirolimus inhibit tumor macrophage infiltration 
in Xenograft models. Iba-1 signal on IHC of tumor samples from 
mice treated with control (Con), sirolimus (Sir), PLX, or the both 
on-treatment (A) and 1 week off treatment (B). 18 
 Con       Sir       PLX    PLX/Sir  
PLX              PLX/Sir 
On Treatment                               Off Treatment 
A 
B 
Ib
a-
1 
  
Ib
a-
1 
Fig. 2. Effect of PLX and sirolimus treatment on MPNST 
xenografts. 
Treatment with 
PLX 
alone, 
or in 
combination with sirolimus was stopped on day 24 as 
depicted by the arrow. 
18 
Tumor  
Vol 
(mm
3) 
Time (Days)   
Fig. 3. PLX and sirolimus inhibit tumor macrophage infiltration 
in Xenograft models. Iba-1 signal on IHC of tumor samples from 
mice treated with control (Con), sirolimus (Sir), PLX, or the both 
on-treatment (A) and 1 week off treatment (B). 18 
 Con       Sir       PLX    PLX/Sir  
PLX              PLX/Sir 
On Treatment                               Off Treatment 
A 
B 
Ib
a-
1 
  
Ib
a-
1 
Fig. 2. Effect of PLX and sirolimus treatment on MPNST 
xenografts. 
Treatment with 
PLX 
alone, 
or in 
combination with sirolimus was stopped on day 24 as 
depicted by the arrow. 
18 
Tumor  
Vol 
(mm
3) 
Time (Days)   
Fig. 3. PLX and sirolimus inhibit tumor macrophage infiltration 
in Xenograft models. Iba-1 signal on IHC of tumor samples from 
mice treated with control (Con), sirolimus (Sir), PLX, or the both 
on-treatment (A) and 1 week off treatment (B). 18 
 Con       Sir       PLX    PLX/Sir  
PLX              PLX/Sir 
On Treatment                               Off Treatment 
A 
B 
Ib
a-
1 
  
Ib
a-
1 


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•
Result in sustained inhibition of tumor macrophage infiltration in MPNST
xenografts.
Taken collectively, these results provide evidence that combination therapy with Turalio® 
and Sirolimus has potent activity in MPNST and make testing this combination in patients 
the next logical step. We propose to translate these positive preclinical findings by testing 
the combination in a phase I/II clinical study in patients suffering from this disease. 
3.
INVESTIGATIONAL AGENT
3.1 
Pharmacology 
Turalio® is an achiral, organic molecule with molecular weight of 418 g/mol and has no 
functional groups that would be expected to confer high aqueous solubility. The active 
pharmaceutical ingredient (API) is available as an HCl salt. Turalio® is a selective inhibitor 
of FMS (CSF1R, the receptor for colony stimulating factor [CSF-1, also known as 
macrophage-colony stimulating factor, M-CSF], as well as the ligand interleukin 34 [IL-
34], KIT (the receptor for stem cell factor, SCF), and oncogenic Flt3 (the receptor for Flt3 
ligand) activity intended for oral administration.  
3.2 Preclinical Data for Turalio® 
Two high-dose GLP 4-week general toxicology studies were conducted with daily oral 
gavage administration of Turalio® (once daily [QD] in rats and twice daily [BID] in dogs) 
at doses of 20, 60, and 200 mg/kg/day in rats and 50, 100, and 300 mg/kg/day in dogs, with 
16-day (rat) or 14-day (dog) recoveries. Neither a no-effect-level (NOEL) nor a no-
adverse-effect-level (NOAEL) of Turalio® could be determined in either species due to
toxicity. Significant adverse test article-related observations appear to be related to
Turalio®-mediated inhibition of Fms and Kit kinases. Turalio®-related histopathologic
observations included testicular spermatagonia reduction, bone marrow hypocellularity,
thymic lymphoid reduction, bone hyperostosis and hypertrophy, ovarian follicular
degeneration, and liver hepatocellular hypertrophy. All findings were partially or fully
reversible.
Two additional GLP toxicology studies at lower dose levels involved daily oral gavage 
administration of Turalio® HCl for 4 weeks (QD in rats and dogs) at doses of 0.5, 2, and 
10 mg/kg/day in rats and 1, 6, and 30 mg/kg/day in dogs, with 8-week recoveries. The 
NOAELs of Turalio® were determined to be 10 mg/kg/day in rats and 6 mg/kg/day in dogs 
in these additional studies. All adverse findings were fully reversible, including testicular 
spermatagonia reduction in dogs.  
Two 13-week GLP toxicology studies involved daily oral gavage administration of 
Turalio® HCl for 13 weeks (QD in rats and dogs), with 8-week recoveries at doses of 0.5, 
4 and 20 mg/kg/day in rats and 1, 6, and 30 mg/kg/day in dogs. NOAELs were determined 
to be 4 mg/kg/day in rats and 6 mg/kg/day in dogs. No new target organ toxicities were 
seen in either study. In rats, anemia, and bone marrow depletion, and hepatocellular 
vacuolation associated with increased liver enzymes were seen. In dogs, findings of 


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reproductive toxicity (spermatogonial reduction) and increased incidence of emesis were 
seen at the 30 mg/kg dose level, which were reversible.  
Potential effects of Turalio® on embryofetal development in rats were assessed at 4, 10, 
and 40 mg/kg/day. Based on changes in hematology parameters at 40 mg/kg/day in the 
dams, and fetal external and visceral malformations and skeletal developmental variations 
(findings primarily related to decreases in ossification) in the fetuses at 40 mg/kg/day, a 
dose level of 10 mg/kg/day was considered to be the NOAEL. 
Turalio® was not mutagenic or clastogenic in the Ames, chromosomal aberration and 
micronucleus tests, and showed no potential to cause phototoxicity in vitro in the NIH 3T3 
fibroblast assay. 
3.3 Clinical Data to Date for Turalio® 
Turalio® was recently approved by FDA for advanced TGCT.  Turalio® can cause hepatic 
adverse reactions, including liver enzyme abnormalities or mixed and cholestatic 
hepatotoxicity. Serious and prolonged hepatotoxicity with ductopenia and/or cholestasis 
has been observed in subjects treated with pexidartinib. In addition, Turalio® is currently 
being studied in combination with other agents. Additionl details of hepatic adverse 
reactions, as well as any other adverse reaction are provided in the currently approved 
Investigators Brochure.  
3.4 Other Agent - Sirolimus 
Sirolimus is a macrocyclic lactone that binds to FK-506 binding protein 12 and inhibits 
mammalian target of rapamycin (mTOR) resulting in cell-cycle arrest and apoptosis.  
Sirolimus is currently approved as an immunosuppressive agent for organ transplantation 
and more recently, as a component of cardiac arterial stents because of its potent 
antiproliferative effects on fibroblasts responsible for restenosis after such a procedure (26) 
Sirolimus is commonly administered orally on a daily basis, in doses ranging from 2 to 40 
mg/day.  
Sirolimus has been also evaluated in a phase I clinical trial in advanced cancer patients by 
Cohen et al. with a similar toxicity profile and pharmacokinetics compared with other 
mTOR inhibitors (27). In addition, there are several clinical trials evaluating daily 
Sirolimus in combination with other cancer therapies in advanced solid tumors (28 – 30). 
Sirolumus at a daily dose of 4 to 6 mg has been utilized in most of these trials with 
pharmacodynamics suppression of S6K1 observed, with one trial documenting 
pharmacodynamic efficacy at a daily dose of 5 mg and not at 2mg (30).  


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4.
STUDY DESIGN
4.1 
General Design 
Phase 1 
The objective of this study is to determine an acceptable dose combination of Sirolimus 
and Turalio®. Patients will be treated with combination therapy at the designated dose 
levels depicted in Table 1 based on a 28 day cycle. Given that Sirolimus is prescribed up 
to doses of 6mg daily and dosed by trough levels, and the MTD for Turalio® from 
clinical studies on solid organ malignancies is 1000mg per day, we will initiate treatment 
at dose level 2 (2mg of Sirolimus in combination with 800mg of oral Turalio® daily, 
Table 1). Since these doses are well tolerated individually, we do not anticipate 
significant toxicities at this combination dose. 
Table 1: Cohort dose levels 
Treatment will continue until evidence of unacceptable toxicity, disease progression, or 
death. The maximum tolerated dose (MTD) combination is defined as the dose 
combination associated with a target probability of dose limiting toxicity of 0.25.  Dose-
limiting toxicity (DLT) is defined in section 5.2.  The MTD will be estimated using the 
time to event continual reassessment method (TITE-CRM).  The TITE-CRM has the same 
advantages as the continual reassessment method (CRM) compared to conventional rule-
based designs.  First, they have been shown to have better performance than the 3+3 design 
and to treat fewer patients at suboptimal doses.  Second, they allow for the specification of 
a fixed sample size for the trial. Third, they can assign doses after the outcome of every 
patient is observed using all prior toxicity information in contrast to limiting the toxicity 
information from the previous assignments.  In addition to these advantages, the TITE-
CRM compared to the CRM can use the patient’s partial information before a complete 
follow-up is achieved while allowing for a longer toxicity evaluation window beyond the 
first cycle to account for late onset toxicities.  Thus, we can conduct the trial in a continuous 
fashion without having patients being turned away due to waiting time.  While we expect 
the majority of toxicities to occur in the first cycle of treatment, there is the possibility of 
toxicities in the second cycle of treatment.  Thus, the toxicity evaluation period is 8 weeks.  
In addition, because the MTD is estimated from partial data, final data may show that 
patients have been treated with a dose exceeding the MTD.  To reduce the potential for 
Dose Level 
  Sirolimus Dose 
Turalio®Dose 
1 
2mg 
600mg 
2 
2mg 
800mg 
3 
2mg 
1000mg 
4 
4mg 
1000mg 
5 
6mg 
1000mg 


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these events, we impose a minimum of 2 weeks of observation between consecutive 
patients.  Patients who discontinue treatment because of progression of disease or death 
unrelated to treatment without experiencing a DLT will be censored at the time of their last 
DLT assessment and included up to the point of their last assessment.  If the last assessment 
occurs prior to the 4 week DLT assessment, that is, prior to the end of the first cycle of 
treatment, the patient will be replenished. To the contrary, if the last assessment occurs 4 
weeks or after, that is, after the end of the first cycle of treatment assessment and the patient 
received at least 80% of the planned doses of Sirolimus and Turalio®  the patient will not 
be replenished. Upon Daiichi Sankyo’s request, CUMC will provide updates for the total 
number of patients enrolled in the study.    
The TITE-CRM with an empiric dose-toxicity model, a linear weight function and a normal 
prior distribution on the parameter with mean 0 and variance of 1.34 is used.   The dose-
toxicity model is calibrated such that the method will eventually select a dose that yields 
between 18% and 32% DLT (31, 32).  The design does not allow for dose skipping or dose 
escalation immediately after a DLT is observed (33). The performance of the TITE-CRM 
is assessed under five potential scenarios with scenarios 3 and 4 being the most likely. The 
operating characteristics of our design given 2000 simulations are displayed in Table 2.  
With 18 patients, the design selects the correct MTD with probabilities over 53% for all 
scenarios.  The scenarios were selected to have neighboring doses with DLT rates within 
15% of the MTD rate. If the neighboring doses have DLT rates significantly different from 
the target of 25%, the probability of correct selection will be improved.  Likewise, if the 
neighboring doses have DLT rates very similar to the target rate, the probability of correct 
selection will worsen.   
Doses of Sirolimus 
Doses of Turalio® 
Dose Level 
2mg 
600mg 
1 
2mg 
800mg 
2 
2mg 
1000mg 
3 
4mg 
1000mg 
4 
6mg 
1000mg 
5 
Scenario 1 
DLT rate 
25% 
40% 
55% 
65% 
80% 
P(Selection) 
74% 
24% 
2% 
0% 
0% 
Scenario 2 
DLT rate 
10% 
25% 
40% 
55% 
65% 
P(Selection) 
21% 
55% 
22% 
2% 
0% 
Scenario 3 
DLT rate 
5% 
10% 
 25% 
40% 
55% 
P(Selection) 
1% 
23% 
53% 
21% 
2% 
Scenario 4 
DLT rate 
2% 
5% 
10% 
25% 
40% 
P(Selection) 
0% 
2% 
26% 
53% 
19% 
Scenario 5 


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DLT rate 
1% 
2% 
5% 
10% 
25% 
P(Selection) 
0% 
0% 
3% 
30% 
66% 
Table 2: Probabilities of Selection under 5 different scenarios 
Figure 4 below summarizes the observations from a simulated trial using the TITE-
CRM method. Trial simulation uses toxicity scenario 4 of Table 2, where the true MTD 
is dose level 4.  The x-axis represents the study time in weeks, the y-axis indicates the 
dose level assigned to each patient. Each number represents a patient in chronological 
order.  Numbers represent patients enrolled at particular dose level and circled number 
indicates the toxicity time (if observed) for a particular patient. For example patients 
1 and 2 were assigned to dose level 2 (the initial dose) and showed no toxicity in the 
first 4 weeks. Patients 3 and 4 entered on weeks 6 and 8, and were assigned to dose 
level 3 and showed no toxicity by study week 10.  Due to the lack of DLTs at previous 
dose levels, patients 5 and 6 started on weeks 10 and 12 and were assigned dose level 
4. None of the patients showed toxicity by study week 14 and patient 7 was assigned
to dose level 5. Between weeks 14 and 16 one DLT was observed from patient 5.  Thus,
on week 16 the dose was de-escalated to dose level 3, which was assigned to patient
8. From weeks 18 to 24, Patients 9 to 12 were assigned to dose level 4.  Given no new
DLTs, the dose was escalated to dose level 5 for patients 13 and 14 enrolled at week
26 and 28. Patient 13 had a DLT by week 30 when patient 15 was enrolled.  Thus,
patients 15 to 18 enrolled in weeks 30 to 36 were assigned to dose level 4.  Patient 14
who was assigned to dose level 5 had a DLT during that period, but the dose was not
lowered.  By the end of the trial, DLTs were reported from three patients: one at dose
level 4 (out of 10), and two (out of 3) at dose level 5. The recommended MTD for this
simulated trial was dose level 4. The posterior DLT probability and the 90%
probability interval associated with dose level 4 were of 18.6% (6%, 37%).


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Figure 4: Simulated Trial Using Time to Event Continuous Reassessment Method. Each number 
represents an enrolled patient while encircled number depicts time at which toxicity experienced by that 
patient. 
Phase 2 
The primary outcome measure is progression free survival (PFS) in patients with MPNST 
at the recommended dose determined from the Phase 1 study, Dose level 3 (1000mg of 
Turalio® orally total daily in combination with 2mg of Sirolimus orally once daily). 
Progression free survival is defined as the time from the start of treatment until disease 
progression or death from any cause.  Patients who have not progressed will be censored 
at the date of their last follow-up. Patients will be evaluated weekly for the first three weeks, 
at least every other week during the first two cycles and then at the beginning of every 
subsequent cycle. Tumor response will be assessed by CT scans performed every six weeks 
for the first six months, every eight weeks for the following six months, and then every 12 
weeks thereafter using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. 
Assuming a median PFS of 6 weeks in patient treated with the standard of care (23), with 
a sample size of 25, we have 90% power to detect a difference of 12 weeks in median PFS 
(6 weeks versus 18 weeks) given a 2-sided test with an alpha of 0.05.  
Patients will be required to obtain research-specific biopsies as follows: 
1) Baseline biopsy of a target lesion
2) Repeat biopsy during last week of cycle 1 for pharmacodynamic analysis
3) Optional biopsies at time of progression


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All biopsies will attempt to obtain 4-5 cores. Two of the cores will be processed for 
formalin fixation and 2-3 will be frozen in liquid nitrogen for exploratory analyses.  
4.2 
Dose Limiting Toxicities for Phase I 
All patients who receive at least one dose of both study drugs will be evaluable for toxicity. 
In order for a patient to be evaluable for DLT assessments, the patient must either incur a 
DLT during the DLT evaluation period or have received at least 80% of the planned doses 
of Sirolimus and Turalio®. Patients who do not fulfill one of these criteria should be 
considered non-evaluable for DLT assessment purposes, and be replaced. 
A DLT is defined as an AE assessed as being possibly, probably, or definitely related to 
study drug administration that is:  
•
Not due to the underlying malignancy;
•
Has no clear evidence of an alternative etiology; and
•
Meets one of the following CTCAE v.4.03 criteria during the first 56 days of Turalio®
and Sirolimus administration:
•
Any Grade ≥ 4 hematologic toxicity except grade 4 lymphopenia
•
Grade 3 neutropenia with fever
•
Grade 3 thrombocytopenia with clinically significant bleeding
•
Any circumstance that results in dose reduction.
•
Any Grade ≥ 3 non-hematologic toxicity except:
•
Nausea, vomiting, and/or diarrhea of Grade 3 severity that resolves within 3
days with optimal prophylaxis and/or treatment.
•
Grade 3 fatigue that resolves to Grade ≤ 2 within 2 days.
•
Grade ≥3 alkaline phosphatase that is related to underlying malignancy
(eg, bone metastasis)
•
For hypercholesterolemia, hypertriglyceridemia, and hyperglycemia if
unresolved after appropriate treatment with standard of care.


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Handling of product specific AESIs (Adverse Events of Special Interest) 
All AESIs defined in the study protocol and noted below should be collected and be 
exchanged between the Parties within the process and timeframes outlined in the Section - 
Exchange of Safety Information from Investigator/Institution to DSI (please see  below): 
•
AESI
o
Hepatic events (both serious and non-serious) which meet the potential Hy’s
Law criteria defined as an elevated (ALT and/or AST) ≥3 x ULN with
simultaneous total bilirubin ≥2 x ULN, regardless if it is due to disease
progression per Investigator assessment, that may occur at different time
points during the study conduct, should always be reported to DSI.
4.3 
Number of Patients  
Approximately 43 evaluable patients are planned for enrollment. 
Phase I:  
18 patients 
Phase II: 
25 patients 
5.
SUBJECT SELECTION AND WITHDRAWAL
5.1 
Inclusion Criteria 
5.1.1. Disease site/type with pathologic confirmation of diagnosis at participating cancer 
site.  
Note: If recurrence occurred  greater than two years after resection, a biopsy to confirm 
recurrence should be performed and used for confirmation of diagnosis at the participating 
site. 
Phase 1: 
Advanced, unresectable sarcoma (any subtype, except for patients 
with pigmented villonodular synovitis for which metastatic disease 
is required). 
Phase 2: 
Advanced, unresectable malignant peripheral nerve sheath tumors 
(MPNSTs) 
5.1.2. Extent of disease 
Unresectable 
5.1.3. Allowable prior therapy 
Phase 1: 
Progressed on standard of care therapy, if one is available. 


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Phase 2: 
MPNST with 0-3 prior cytotoxic systemic therapies (no prior 
radiotherapy is necessary). 
5.1.4. ECOG performance status 
0, 1, or 2 
5.1.5. Age greater or equal to 18 years. Because no dosing or adverse event data are 
currently available on the use of Turalio® in combination with Sirolimus in patients 
<18 years of age, children are excluded from this study, but will be eligible for future 
pediatric trials. 
5.1.6. Presence of measurable lesions by Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1 
5.1.7.  Allowable laboratory values with date range 
•
Labs should be done within 14 days of starting Cycle 1 Day 1 treatment
•
ANC ≥1.5 X 109/L, Hgb >10 g/dL, and platelet count ≥100 X 109/L
•
AST/ALT/ALP/GGT ≤ upper limit of normal (ULN)
•
Total bilirubin and direct bilirubin ≤ ULN
•
Patients with hyperbilirubinemia clinically consistent with an inherited disorder of
bilirubin metabolism (e.g., Gilbert syndrome) will be eligible at the discretion of
the principal investigator if total bilirubin is  ≤ 1.5 X ULN
•
Albumin ≥ 3.0g/dL.
•
Creatinine  ≤ 1.5 X ULN or calculated creatinine clearance (CrCl) > 60 mL/min
using the Cockcroft-Gault formula less than eight days prior to start of treatment.
5.1.8.  Women of child-bearing potential must have a negative serum pregnancy test at 
screening and must agree to use an effective form of contraception from the time of 
the negative pregnancy test and for a minimum of 3 months after the last dose of 
study drug. Effective forms of contraception include abstinence, hormonal 
contraceptive (injectable or implantable) in conjunction with a barrier method, a 
double barrier method, diaphragm or cerival cap with a cream or gel that kills sperm, 
bilartreal tubal occlusion, vasectomy, or an intrauterine device (IUD). Women of 
non-child-bearing potential must have been postmenopausal for ≥ 1 year or 
surgically sterile. The effects of Turalio® and Sirolimus on the developing human 
fetus are unknown.  For this reason women of child-bearing potential and men must 
agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry, for the duration of study participation and 3 months 
after completion of Turalio® and Sirolimus administration.  Should a woman 
become pregnant or suspect she is pregnant while she or her partner is participating 
in this study, sshe should inform her treating physician immediately.  Men treated 
or enrolled on this protocol must also agree to use adequate contraception prior to 


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the study, for the duration of study participation, and 3 months after completion of 
Turalio® and Sirolimus administration. 
5.1.9.  Fertile men must agree to use an effective method of birth control during the study 
and for up to 3 months after the last dose of study drug. 
5.1.10. Willingness and ability to provide written informed consent prior to any study-
related procedures and to comply with all study requirements. 
5.1.11. For phase 2 specifically, agree to pre- and on-treatment tumor biopsies. If subject 
is unable to undergo paired research biopsies safely, subject may enroll onto the study 
without a research biopsy(ies) pending number of evaluable paired biopsies available at 
the discretion of the Principal Investigator. 
5.1.12. Prior treatment-related AEs must be ≤ grade 1 (CTCAE v4.0), except alopecia, at 
time of initiating study drug. 
5.2        Exclusion Criteria 
5.2.1 
Prior treatments – 
i. Patients who have had systemic cytotoxic therapy or radiotherapy within 4
weeks (6 weeks for nitrosoureas or mitomycin C) or targeted therapy with small
molecule inhibitors within 2 weeks prior to entering the study.
ii. Patients who have not recovered from adverse events (≤ grade 1; except
alopecia) due to agents administered more than 4 weeks earlier.
iii. Patients need to be free of adverse effects (≤ grade 1; except alopecia) from
prior treatments for at least 14 days from cycle 1 day 1 of Turalio® and
Sirolimus.
5.2.2    
Patients who are receiving any other investigational agents concurrently. 
5.2.3    
Concomitant treatment with other anti-neoplastic agents (hormonal therapy 
acceptable). 
5.2.4    
Patients with symptomatic brain metastases. Subjects with untreated brain 
metastasis ≤ 1 cm can be considered eligible if deemed asymptomatic by the 
investigator upon consultation with the medical monitor and do not require 
immediate radiation or steroids. Subjects with brain metastasis that is treated 
and stable for 1 month may be considered eligible if they are asymptomatic and 
on stable dose of steroids or if they do not require steroids following successful 
local therapy. 


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5.2.5    
History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to Turalio® or Sirolimus. 
5.2.6   
For Phase 2 - Prior exposure to a receptor tyrosine kinase or mammalian target 
of Rapamycin inhibitor. 
5.2.7  
Pregnant women are excluded from this study because Turalio® and Sirolimus 
are agents with the potential for teratogenic or abortifacient effects.  Because 
there is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with Turalio® and Sirolimus, 
breastfeeding should be discontinued if the mother is treated with Turalio® and 
Sirolimus. 
5.2.8    
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, active liver disease, symptomatic congestive heart failure, unstable 
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
5.2.9 
Active secondary malignancy unless the malignancy is not expected to interfere 
with the evaluation of safety and is approved by the Sponsor. Examples of the 
latter include basal or squamous cell carcinoma of the skin, in-situ carcinoma 
of the cervix, and isolated elevation of prostate-specific antigen. Subjects with 
a completely treated prior malignancy and no evidence of disease for ≥ 2 years 
are eligible. 
5.2.10 
Major surgical procedure or significant traumatic injury within 14 days of 
initiating study drug or anticipation of the need for major surgery during the 
study. 
5.2.11 
Previous radiotherapy to 25% or more of the bone marrow and/or radiation 
therapy within 28 days prior to study entry. 
5.2.12 
Inability to swallow capsules, or refractory nausea and vomiting, 
malabsorption, an external biliary shunt, or significant bowel resection that 
would preclude adequate absorption. 
5.2.13 
Congestive heart failure (CHF) New York (NY) Heart Association class III or 
IV; unstable coronary artery disease (myocardial infarction [MI] more than 6 
months prior to study entry is permitted); or serious cardiac arrhythmia. 
5.2.14 
Baseline QTcF ≥ 450 ms (males) or ≥ 470 ms (females) 
5.2.15 
HIV-positive patients on combination antiretroviral therapy are ineligible 
because of the potential for pharmacokinetic interactions with PLX3997.  In 
addition, these patients are at increased risk of lethal infections when treated 
with marrow-suppressive therapy.  Similarly, patients with chronic or acute 
hepatitis C virus (HCV) or hepatitis B virus (HBV) infection are also ineligible. 
Prior hepatitis infection that has been treated with highly effective therapy with 


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no evidence of residual infection and with normal liver function (ALT, AST, 
total and direct bilirubin ≤ ULN) is allowed. 
5.2.16 
Of the five major CYP isoforms, 3A4 (BFC) may be involved in Phase I 
metabolism of Turalio®, with possibly CYP1A2 playing a minor role. Until 
information regarding exposure toxicity and exposure-response relationships 
are available with Turalio®, concomitant strong CYP3A4 inhibitors and 
inducers are not permitted in the event they alter the systemic exposure to 
Turalio® (see Attachment 1 for a list of common CYP3A4 inhibitors and 
inducers). These include anticonvulsants, mycin antimicrobials, and 
antiretrovirals. Some common examples include inhibitors such as 
erythromycin, fluoxetine, gemfibrozil, and inducers such as rifampicin, 
carbamazepine, phenytoin, efavirenz, and nevirapine.  
If concomitant use with a strong CYP3A inhibitor, UGT inhibitor, or acid 
reducing agent cannot be avoided, see below for guidance taken from the 
approved USPI.  
Avoid concomitant use of Turalio®with strong CYP3A inhibitors or UGT 
inhibitors during treatment with Turalio®. If concomitant use with a strong 
CYP3A inhibitor or UGT inhibitor cannot be avoided, reduce the Turalio® dose 
according to the recommendations in table below. If concomitant use of a strong 
CYP3A inhibitor or UGT inhibitor is discontinued, increase the Turalio® dose 
(after 3 plasma half-lives of the strong CYP3A inhibitor or UGT inhibitor) to 
the dose that was used before starting the inhibitor [see Clinical Pharmacology 
(12.3)]. 
Recommended Dosage Reductions for Turalio®for Concomitant Use of 
Strong CYP3A Inhibitors or UGT Inhibitors 
Planned Total Daily 
Dose 
Modified Total Daily 
Dose 
Administration of 
Modified Total Daily 
Dose 
800 mg 
400 mg 
200 mg twice daily 
600 mg 
400 mg 
200 mg twice daily 
400 mg 
200 mg 
200 mg once daily 
* Planned total daily dose refers to recommended dose reductions for Turalio®
for adverse reactions based on dosing recommendations in Section 8.2 Dose
Modificiations
Avoid the concomitant use of proton pump inhibitors (PPI) while taking 
Turalio®. As an alternative to a PPI, administer Turalio® 2 hours before or 2 
hours after taking a locally-acting antacid, or if using a histamine 2 (H2)-


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receptor antagonist, administer Turalio® at least 2 hours before or 10 hours 
after taking an H2-receptor antagonist. 
Concomitant treatment is permitted if the medication is not expected to interfere 
with the evaluation of safety or efficacy of the study drug. During the study, if 
the use of any concomitant treatment becomes necessary (e.g., for treatment of 
an adverse event), the treatment must be recorded on the eCRF, including the 
reason for treatment, generic name of the drug, dosage, route, and start and stop 
dates of administration.  
Sirolimus undergoes extensive hepatic and intestinal metabolism via CYP3A4 
and CYP3A5, as well as excretion by P-glycoprotein. Strong CYP3A inhibitors 
such as ketoconazole or grapefruit juice are not permitted. Patients should be 
monitored for supratherapeutic toxic levels of Sirolimus and Turalio®. As bone 
marrow suppression including anemia, neutropenia, and thrombocytopenia 
have been reported in patients receiving Sirolimus monotherapy, these adverse 
effects may be exacerbated in combination with Turalio® for which patients 
will be closely monitored. 
5.2.17. 
Any patients on warfarin therapy. 
5.2.18. 
Hepatobiliary diseases including biliary tract diseases, autoimmune hepatitis, 
inflammation, fibrosis, cirrhosis of liver caused by viral, alcohol, or genetic 
reasons. Gilbert’s disease is allowed if TBil is ≤ 1.5 × ULN. 


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If concomitant use with a strong CYP3A inhibitor, UGT inhibitor, or acid reducing agent 
cannot be avoided, see below for guidance taken from the approved USPI 
Recommended Dosage Reductions for Turalio®for Concomitant Use of 
Strong CYP3A Inhibitors or UGT Inhibitors 
Planned Total Daily 
Dose 
Modified Total Daily 
Dose 
Administration of 
Modified Total Daily 
Dose 
800 mg 
400 mg 
200 mg twice daily 
600 mg 
400 mg 
200 mg twice daily 
400 mg 
200 mg 
200 mg once daily 
* Planned total daily dose refers to recommended dose reductions for Turalio®
for adverse reactions based on dosing recommendations in Section 
8.2 Dose Modificiations 
Avoid the concomitant use of proton pump inhibitors (PPI) while taking 
Turalio®. As an alternative to a PPI, administer Turalio® 2 hours before or 2 
hours after taking a locally-acting antacid, or if using a histamine 2 (H2)-
receptor antagonist, administer Turalio® at least 2 hours before or 10 hours 
after taking an H2-receptor antagonist. 
7.3 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue until one 
of the following criteria applies: 
o
Disease progression
o
Therapy may be permitted beyond progression if patient is deriving clinical benefit
after initial tumor growth or ambiguity regarding the existence of disease
progression in consultation with the principle investigator, sponsor, and CUMC
IRB. If subsequent imaging confirms tumor growth, progression will be back dated
to the prior scan. If patient agrees to treatment beyond progression, the patient will
be required to sign a “Treatment Beyond Progression” informed consent form.
o
Intercurrent illness that prevents further administration of treatment
o
Unacceptable adverse events(s)
o
Patient decides to withdraw from the study
o
General or specific changes in the patient's condition render the patient
unacceptable for further treatment in the judgment of the investigator
o
Major protocol violation


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7.4 
Duration of Follow Up 
Patients will be followed after completion or removal from study or until death, whichever 
occurs first.  Patients removed from study for unacceptable adverse events will be followed 
until resolution or stabilization of the adverse event. Thereafter, patients will be contacted 
by phone every 3 months during year 1 and every 6 months thereafter to obtain information 
about subsequent treatment(s) and survival status. 
7.5 
Criteria for Removal from Study 
The reasons a patient may discontinue or be withdrawn from the study include, but are 
not limited to, adverse event, clinically significant disease progression, patient request, 
investigator decision, protocol violation, patient noncompliance, and study termination by 
the Sponsor or institutional review board (IRB)/independent ethics committee (IEC). 
When a patient discontinues or is withdrawn, the investigator will notify the Sponsor and 
should perform the procedures indicated in the End of Study column in the Schedule of 
Events within 28 days after discontinuation of study drug and before initiation of any new 
anti-cancer therapy. Follow-up information will be obtained for patients who discontinue 
their participation in or are withdrawn from the study. 
Patients withdrawn from the study for reasons other than toxicity or clinically significant 
disease progression (e.g., protocol violation or noncompliance) may be replaced at the 
discretion of the medical monitor and the investigator. Study drug administration may be 
discontinued for an adverse event or at the discretion of the investigator. 
The consequence of withdrawal of all consent by a patient will be that no new information 
will be collected from that patient and added to the existing data or any database. However, 
every effort will be made to follow all patients for safety. 
8.
DOSING DELAYS/DOSE MODIFICATIONS
8.1 
Phase 1 Dose Modification 
All patients may have dose modifications at any time. During Cycle 1 in the phase 1 
portion, however, the DLT must be recorded for safety purposes prior to dose reduction. 
Patients may have drug held for any reason for up to 14 days before discontinuing study 
treatment. Refer to Tables 4 - 7 below for specific dose modification instructions. 
Patients will undergo therapeutic monitoring with trough levels of Sirolimus on day 2 of 
cycle 1 before receiving daily dose of Sirolimus on day 2 (+2 day window), day 8, day 15, 
and day 22 of Cycle 1, on day 1 of each subsequent cycle, unless clinically indicated, and 
during the End-of-Study visit. Trough levels may be measured at other time points as 
clinically indicated. As levels >18.0g/L are more likely to be associated with an adverse 
events, dosing of Sirolimus will be held and/or reduced in the case of trough levels 
>18.0g/L as indicated in the dose modification table (Table 4). Deviation of this dose
modification can be done at the discretion of the treating investigator in discussion with
the study principal investigator.


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Sirolimus Monitoring and Dose Modification 
Trough level > 18g/L 
First Event 
Hold Sirolimus for three days and re-measure trough level on fourth 
day (+2 day window): 
•
If ≤ 18g/L, reinstitute drug at original dose
•
If > 18g/L hold drug for additional three days and re-
measure trough level on fourth day (+2 day window).
Repeat dose interruption for additional three days and re-
measure trough level the following day until trough level ≤
18g/L, at which time re-institute Sirolimus at next lower
dose. Dose reduction constitutes a DLT.
Second Event 
Hold Sirolimus for three days and re-measure trough level on fourth 
day (+2 day window): 
•
If ≤ 18g/L, reinstitute Sirolimus at next lower dose. Dose
reduction constitutes a DLT.
•
If > 18g/L hold Sirolimus for additional three days and re-
measure trough level on fourth day (+2 day window).
Repeat dose interruption for additional three days and re-
measure trough level the following day until trough level ≤
18g/L, at which time re-institute Sirolimus at next lower
dose. Dose reduction constitutes a DLT.
Table 4. Sirolimus level dose modification recommendations 
8.1.1 Dose Modification for Hepatotoxicity, Nausea/Emesis, and Hyperglycemia 
8.1.1.1 
Hepatotoxicity –  Turalio® and Sirolimus should be discontinued if 
hepatotoxicity is observed as detailed in Table 5. 
Reductions or interruptions of the Turalio® dose for toxicity may take place at any time 
during the study according to the guidelines in Tables 5 and 6. Dose reduction/interruption 
guidelines for hematologic and nonhematologic treatment-related TEAEs are based on 
severity. Dose interruptions can be implemented at the discretion of the treating 
Investigator to manage intolerable or clinically significant toxicity. If a dose interruption 
is required, study assessments should be performed as scheduled, irrespective of the study 
drug delay, with the exception of PK assessments, which should be deferred until treatment 
is resumed. Interruptions due to toxicity lasting >14 d require treatment discontinuation 
unless the medical monitor approves continuation. 


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Table 6: 
Additional Liver Evaluation 
Evaluation 
Comments 
Increase frequency of testing liver chemistries 
to twice per wk, including INR, PT, total and 
indirect bilirubin, and albumin and continue 
until liver chemistries have stabilized, and 
then reduce to weekly until liver chemistries 
return to normal or baseline. 
Turalio® may be started after liver function 
tests recover to Grade 0 to 1 or baseline level, 
and in consultation with the Principal 
Investigator. 
Detailed history focusing on medications in a 
weekly clinic visit and substances used: 
alcohol, change in medication dosages, new 
medications added, attention to use of 
acetaminophen, OTC medication use, and 
recreational drug use. Check for change in diet 
or use of dietary supplements, with particular 
attention to dose and duration of any herbal 
product.  
Suspect medications will be discontinued or 
substituted for if possible. 
Detailed 
medical 
history 
and 
physical 
examination seeking new abnormalities in a 
weekly clinic visits. Frequency of visits as 
detailed in Table 5. 
Evaluate abnormalities found. 
Full serological evaluation for hepatitis A, B, 
C, and E (IgG and IgM). Check for 
autoimmune 
hepatitis 
with 
serological 
laboratory studies. 
If viral hepatitis or autoimmune hepatitis 
suggested, 
have 
patient 
evaluated 
by 
hepatologist. 
Liver ultrasound performed to evaluate liver 
and biliary tree. 
Evaluate any abnormalities found. 
Check history for exposure to chemical 
agents. 
Remove chemical exposure and have patient 
seen by hepatologist. 
Obtain hepatology consult if liver function 
continues to rise beyond 14 d. 
)Daiichi Sankyo Safety Lead, Jason Jiang at 
jjiang@dsi.com  
We request that cases be discussed with the Principal Investigator as defined in the 
protocol whenever investigational product is being held for liver function test 
abnormality. 
Ig = Immunoglobulin; INR = international normalized ratio; OTC = over-the-counter. 
For suspected cases of cholestatic liver injury (eg, aminotransferase increase concurrent with 
hyperbilirubinemia, or liver biopsy suggesting cholestasis and/or ductopenia), patients will be 
followed to assess long-term outcome. Additional diagnostic and follow-up procedures might be 
implemented as appropriate to fully assess the event.  


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8.1.1.2 
Nausea and Vomiting – Turalio® may be associated with nausea and/or emesis that 
can arise early in the course of therapy. Sirolimus may also contribute to nausea and 
emesis and may be held as well at the discretion of the treating physician. 
Nausea and Vomiting 
Grade 3 
Hold Turalio® dosing until improved  to grade 1 or baseline. If delay 
<48 hours from start of maximal supportive treatment, then restart at 
cohort with next lower dose for Turalio®. 
If delay for ≥48 hours despite maximal supportive treatment, 
discontinue study treatment. 
Grade 4 
If any grade 4 toxicity despite maximal supportive treatment, 
discontinue study treatment.  
Table 7. Nausea and emesis dose modification recommendations 
8.1.1.3 
Hyperglycemia – immunosuppressive agents, including Sirolimus have been 
associated with hyperglycemia that responds to treatment. 
Hyperglycemia – Assessed by Fasting Blood Glucose and NOT CTCAE grades 
Grade 1 = 140-199 mg/dL Maintain Turalio® and Sirolimus dosing and institute diet 
modifications. Address any underlying contributing factors 
(infection, steroids) and consider initiating blood glucose lowering 
therapy. 
Grade 2 = 200-249 mg/dL Maintain Turalio® and Sirolimus dosing and initiate blood glucose 
lowering therapy. 
Grade 3 = 250-399 mg/dL Hold only Sirolimus dosing until improved to ≤ Grade 1. 
• If ≤7 days, dose reduction is at discretion of treating physician.
• If >7 days, dose reduce to cohort with next lower dose of
Sirolimus.
Grade 4 = 400 mg/dL or 
higher 
OR 
Any hyperglycemia 
leading to diabetic 
ketoacidosis, 
hyperosmolar nonketotic 
Discontinue from study drug treatment. 


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coma, or requiring IV 
insulin infusion. 
 Table 8. Hyperglycemia dose modification recommendations 
Toxicities that occur outside the DLT window will be taken into consideration when determining 
the RP2D. Reduction/interruption of dosing for AEs may take place at any time. Below are 
guidelines for dosage modification for Turalio®–related toxicities as well as guidelines for their 
management. Dose reductions should occur in increments of 200 mg/day, depending on the 
toxicity grade, as noted in Table 9. These parameters are only a guide and are not intended to 
supersede the clinical judgment of the treating physician. All adjustments should be made in 
consultation with the principal investigator. Dosing interruptions longer than three weeks for any 
reason should generally result in discontinuation from the study, unless the patient has 
demonstrated a clinical benefit from therapy and would like to continue dosing with study drug 
after discussion between the investigator and the Sponsor. 
Toxicity 
Grade 
(CTCAE v4) 
Turalio® and 
Sirolimus dose changes 
during current 
treatment period 
Dose adjustments for resumption of treatment 
Hematologic Toxicity 
Any Grade 4,  or Grade 3 neutropenia with fever, or thrombocytopenia with bleeding and except 
for Grade 4 lymphopenia 
1st Appearance 
Interrupt 
until 
ANC 
recovers to ≥ 1X109/L; 
growth factor support 
permitted 
Dose reduce one dose level. If dose level 1 at time of AE, 
discontinue both drugs. 
2nd Appearance 
Interrupt 
until 
ANC 
recovers to ≥ 1X109/L; 
provide growth factor 
support 
Dose reduce one additional dose level. If dose level 1 at time 
of AE, discontinue both drugs. 
3rd Appearance 
Interrupt 
until 
ANC 
recovers to ≥ 1X109/L; 
provide growth factor 
support 
Dose reduce one additional dose level. If dose level 1 at time 
of AE, discontinue both drugs. 
4th Appearance 
Discontinue Permanently N/A 


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Table 9: Recommended Turalio® and Sirolimus Dose Modifications 
Dose interruptions for Grade 2 non-hematologic toxicity for up to 1 week can be implemented at 
the discretion of the treating physician to manage intolerable or clinically significant toxicity. No 
dose reduction is required when resuming treatment. 
8.2 
Phase 2 Dose Modification 
Patients may have dose modifications at any time. Patients may have either drug held for any 
reason for up to 21 days before discontinuing study treatment. Refer to Tables 10 – 14 below for 
specific dose modification instructions. 
8.2.1 Dose Modification for Sirolimus 
Patients will undergo therapeutic monitoring with trough levels of Sirolimus on day 2 of cycle 1 
before receiving daily dose of Sirolimus on day 2 (+2 day window), day 8, day 15, and day 22 of 
Cycle 1, on day 1 of each subsequent cycle, unless clinically indicated, and during the End-of-
Study visit. Trough levels may be measured at other time points as clinically indicated. As levels 
>18.0g/L are more likely to be associated with an adverse event, dosing of Sirolimus will be held
and/or reduced in the case of trough levels >18.0g/L as indicated in the dose modification table
(Table 10). Deviation of this dose modification can be done at the discretion of the treating
investigator in discussion with the study principal investigator.
Non-Hematologic Related Grade 3 or Grade 4 not related to abnormal liver function (start 
symptomatic treatment when possible).   
1st Appearance 
Interrupt until recovered 
(grade 0-1) and provide 
supportive management. 
Dose reduce one dose level. If dose level 1 at time of AE, 
discontinue both drugs. 
2nd Appearance 
Interrupt until recovered 
(grade 0-1) and provide 
supportive management 
Dose reduce one additional dose level. If dose level 1 at time 
of AE, discontinue both drugs. 
3rd Appearance 
Interrupt until recovered 
(grade 0-1) and provide 
supportive management 
Dose reduce one additional dose level. If dose level 1 at time 
of AE, discontinue both drugs. 
4th Appearance 
Discontinue Permanently N/A 


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Sirolimus Monitoring and Dose Modification 
Trough level > 18g/L 
First Event 
Hold Sirolimus for three days and re-measure trough level on fourth 
day (+2 day window): 
•
If ≤ 18g/L, reinstitute drug at 2 mg orally daily.
•
If > 18g/L hold drug for additional three days and re-
measure trough level on fourth day (+2 day window).
Continue  dose hold for up to 21 days total, re-measuring
trough levels every fourth day (+2 day window) until
trough level ≤ 18g/L, at which time re-institute Sirolimus
at 1mg orally daily.
Second Event 
Hold Sirolimus for three days and re-measure trough level on fourth 
day (+2 day window): 
•
If ≤ 18g/L, reinstitute Sirolimus at 1mg orally daily.
•
If > 18g/L hold Sirolimus for additional three days and re-
measure trough level on fourth day (+2 day window).
Continue dose hold for up to 21 days total, re-measuring
trough levels every fourth day (+2 day window) until
trough level ≤ 18g/L, at which time re-institute Sirolimus
at 0.5mg daily.
For Third Event or higher, hold Sirolimus for three days and re-
measure trough level on fourth day (+2 day window). If ≤ 18g/L, 
reinstitute Sirolimus at 0.5mg daily. If Sirolimus trough level is > 
18g/L at the 0.5mg orally daily dose, the patient should 
discontinue study treatment. 
Table 10. Sirolimus level dose modification recommendations 
8.2.2 Dose Modification for Hepatotoxicity, Nausea/Emesis, and Hyperglycemia 
Hepatotoxicity –  Turalio® and Sirolimus should be discontinued if hepatotoxicity is observed as 
detailed in Tables 5 and 6. 
Reductions or interruptions of the Turalio® dose for toxicity may take place at any time during 
the study according to the guidelines in Tables 5 and 6. Dose reduction/interruption guidelines for 
hematologic and nonhematologic treatment-related TEAEs are based on severity. Dose 
interruptions can be implemented at the discretion of the treating Investigator to manage 
intolerable or clinically significant toxicity. Interruptions due to toxicity lasting > 21 d require 
treatment discontinuation unless the medical monitor approves continuation. 


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Nausea and Vomiting – Turalio® may be associated with nausea and/or emesis that can arise 
early in the course of therapy. Sirolimus may also contribute to nausea and emesis and may be 
held as well at the discretion of the treating physician. 
Nausea and Vomiting 
Grade 3 
Hold Turalio® and Sirolimus dosing until improved to grade 1 or 
baseline. If improvement of symptoms in less than 48 hours from start 
of maximal supportive treatment, then restart at 400mg orally in AM 
and 400mg orally in PM daily. 
If symptoms do not improve within 48 hours despite maximal 
supportive treatment, hold Turalio® and Sirolimus, and consult with 
Principal Investigator.  
Grade 4 
If grade 4 toxicity despite maximal supportive treatment, hold 
Turalio® and Sirolimus, and consult with Principal Investigator.  
Table 12. Nausea and emesis dose modification recommendations 
Hyperglycemia – immunosuppressive agents, including Sirolimus have been associated with 
hyperglycemia that responds to treatment. 
Hyperglycemia – Assessed by Fasting Blood Glucose 
Grade 1 = > ULN - 160 
mg/dL 
Maintain Turalio® and Sirolimus dosing and institute diet 
modifications. Address any underlying contributing factors 
(infection, steroids) and consider initiating blood glucose lowering 
therapy. 
Grade 2 = > 160 - 250 
mg/dL 
Maintain Turalio® and Sirolimus dosing and initiate blood glucose 
lowering therapy. 
Grade 3 = > 250-500 
mg/dL 
OR 
Hospitalization indicated. 
Hold only Sirolimus and initiate blood glucose lowering therapy. 
Reinstitute Sirolimus if < Grade 2.  
• If ≤7 days, dose reduction is at discretion of treating physician.
• If >7 days, dose reduce to 1mg orally daily if study related.
Grade 4 = > 500 mg/dL 
OR  
Life threatening 
consequences.  
Discontinue from study drug treatment if AE considered study 
related.  
 Table 13. Hyperglycemia dose modification recommendations 


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8.2.3 Dose Modification for Non-Hematologic Toxicity 
Reduction/interruption of dosing for other AEs may take place at any time. Below are guidelines 
for dosage modification for Turalio®–related toxicities as well as guidelines for their management. 
Dose reductions should depend on the toxicity grade, as noted in Table 14. These parameters are 
only a guide and are not intended to supersede the clinical judgment of the treating physician. All 
adjustments should be made in consultation with the principal investigator. Dosing holds longer 
than 21 days for any reason should generally result in discontinuation from the study, unless 
the patient has demonstrated a clinical benefit from therapy and would like to continue dosing with 
study drug after discussion between the investigator and the Principal investigator. 
Toxicity 
Grade 
(CTCAE v4) 
Turalio® and 
Sirolimus dose changes 
during current 
treatment period 
Dose adjustments for resumption of treatment 
Hematologic Toxicity 
Any Grade 4,  or Grade 3, neutropenia with fever, or thrombocytopenia with bleeding, except for 
Grade 4 lymphopenia 
1st Appearance 
Interrupt 
until 
ANC 
recovers to ≥ 1X109/L; 
growth factor support 
permitted 
Dose reduce Turalio® to 400mg orally in AM and 400mg 
orally in PM daily.  
2nd Appearance 
Interrupt 
until 
ANC 
recovers to ≥ 1X109/L; 
provide growth factor 
support 
If Turalio® total daily dose at 800mg orally, dose reduce 
Turalio® to 200mg in AM and 400mg in PM. If Sirolimus 
2.0mg, decreased to 1.0mg. 
3rd Appearance 
Interrupt 
until 
ANC 
recovers to ≥ 1X109/L; 
provide growth factor 
support 
Discontinue study treatments unless subject deriving 
clinical benefit. Consult with Principal investigator and 
consider decreasing Turalio® to 200mg twice daily and 
decrease Sirolimus to half the dose unless at 0.5mg. 
4th Appearance 
Discontinue Permanently N/A 
Non-Hematologic Related Grade 3 or Grade 4 not related to abnormal liver function (start 
symptomatic treatment when possible).   
1st Appearance 
Interrupt until recovered 
(grade 0-1) and provide 
supportive management. 
Dose reduce Turalio® to 400mg orally in AM and 400mg 
orally in PM daily and Sirolimus to 1.0mg orally in AM.  
2nd Appearance 
Interrupt until recovered 
(grade 0-1) and provide 
supportive management 
Continue Turalio® at 400mg orally in AM and 400mg 
orally in PM daily and dose reduce Sirolimus to 0.5mg 
orally in AM.  


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Table 14: Recommended Turalio® and Sirolimus Dose Modifications 
Dose interruptions for Grade 2 non-hematologic toxicity for up to 1 week can be implemented at 
the discretion of the treating physician to manage intolerable or clinically significant toxicity. No 
dose reduction is required when resuming treatment (unless hepatotoxicity). 
9.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS
9.1 
Adverse Events Most Likely Related to Turalio® and Sirolimus
9.1.1 Turalio® 
For a complete adverse event profile, please refer to IB version 12. Side effects that may 
be seen with Turalio® given by itself or in combination with other anti-cancer treatments. 
Common side effects (≥10% by frequency) associated with the use of Turalio® include the 
following: 
•
Nausea
•
Vomiting
•
Constipation
•
Abdominal pain
•
Abnormal, altered, or loss of sense of taste
•
Decreased appetite
•
Rash
•
Pruritus (itching of skin)
•
Hair color changes (to white or gray; original color usually returns after stopping study
drug)
•
Increases in liver blood tests
•
Fatigue or tiredness
•
Headache (including migraine)
•
Hypertension (high blood pressure)
•
Edema (swelling of tissues in limbs or face)
•
Eye edema (swelling in or around the eyes)
Less common side effects (less than 10%) associated with the use of Turalio® include the 
following: 
3rd Appearance 
Interrupt until recovered 
(grade 0-1) and provide 
supportive management 
Discontinue study treatments. 


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•
Hepatotoxicity (liver injury), which may be serious and fatal
•
Cognitive disorder (includes memory impairment, amnesia, cognitive disorder, attention
deficit hyperactivity disorder, disturbance in attention)
•
Dry mouth
•
Neuropathy (numbness or weakness)
•
Stomatitis (inflammation inside of mouth, usually a small sore or ulcer)
•
Alopecia (loss of hair)
•
Skin color changes
•
Pyrexia (fever)
•
Vision changes (including blurred vision, sensitivity to light, double vision, and reduced
visual clarity)
•
Increase in bilirubin (produced when the liver breaks down red blood cells)
•
Decrease in white blood cell counts (which could include one or more of the following:
white blood cell counts, lymphocytes, neutrophils, leukocytes; this may lead to increased
risk of infection)
•
High cholesterol
Turalio® may cause liver injury, also known as hepatotoxicity. Such an injury can be severe 
and prolonged despite stopping of study medication. The liver injury may be fatal. Should 
your liver tests become abnormal you may be required to have additional monitoring and 
evaluation, which may include a liver biopsy. Treatment may include blood filtering to remove 
waste products of the liver. One patient required a liver transplant. One patient died before the 
liver injury got better. Taking Turalio®  together with other medications may increase the risk of 
severe liver injury. 
Turalio® . This type of rash may sometimes include fever and inflammation of internal organs. 
Animals treated with Turalio®  showed dec rease in the pumping action (contraction) of the heart. 
There have been two reports of reduced ejection fraction (the amount of blood pumped by your 
heart with each beat) in patients receiving Turalio®  at a dose of 3000 mg/day, a much higher dose 
than you will receive. The role of  Turalio® in these events is undetermined at this time. 
The severity of the side effects listed above could range from mild to severe or even life-
threatening. In addition, there may be other risks or side effects from Turalio® that are not listed 
above or unknown at this time.  It is also possible to experience a serious allergic reaction, which 
could become life-threatening or fatal.  Symptoms of an allergic reaction include rash, hives, 
itching, swelling of the mouth, face, lips or tongue, dizziness, low blood pressure, tightness in the 
chest, or trouble breathing. 
Reproductive Risks 
If a patient or partner becomes pregnant or fathers a child while in this research study or 90 days 
following study completion, they must notify the study doctor immediately.  The risk of taking 
this product in pregnant women has not been fully determined from either human studies or animal 
studies.  There is no clinical experience in humans with Turalio®  in pregnant or lactating women.  


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Turalio®  can cause fetal defects in rodents and rabbits, and should be considered potentially 
harmful to the human fetus, with the potential to cause fetal malformations.  As a result, Turalio® 
should not be administered to pregnant women or lactating women who are breastfeeding. Patients 
and partners should avoid becoming pregnant over the course of this study.  Becoming pregnant 
while participating in the study will expose the patient or partner  to a potential loss of the 
pregnancy, or other unknown effects on an unborn child such as, but not limited to, birth defects 
and premature delivery.  They will be withdrawn from the study if they become pregnant or have 
a positive pregnancy test. If they become pregnant, they will be followed until the time the 
pregnancy is completed or terminated in order to collect information about the pregnancy, 
determine the outcome of the pregnancy, childbirth and the health of the baby (first well-baby 
visit). If the pregnancy continues to term, the outcome (health of infant) must also be reported. All 
pregnancy/lactation reports, including pregnancy reports in which the patient or a partner of a 
patient may have been exposed to the Product(s) via either maternal or paternal exposure, lactation 
reports, unintended pregnancy, with or without an associated adverse event, where the fetus could 
have been exposed to the study drug shall be collected.  
In animal studies, Turalio®  caused a decrease in sperm count and changes in the ovaries which were 
reversible at the end of the study. Turalio® may therefore affect fertility in both men and women. If you 
are a male, you may ask your study doctor about sperm banking. 
9.1.2 Sirolimus 
Sirolimus is approved for prophylaxis of organ rejection in patients receiving renal 
transplants. Known toxicities include risk of opportunistic infections, interstitial lung 
disease, hyperlipidemia, risk of malignancy (including lymphoma), proteinuria, mucositis, 
nausea, emesis, diarrhea, edema, elevated liver enzymes, and bone marrow suppression 
including anemia, neutropenia, and thrombocytopenia. 
Side effects that may be seen with Sirolimus given by itself or in combination with other 
anti-cancer treatments. 
Some common side effects (≥30% by frequency) seen with the use of Sirolimus in 
patients with cancer include the following: 
•
Peripheral edema
•
Hypertriglyceridemia
•
Hypercholesterolemia
•
Increased creatinine (kidney dysfunction)
•
Hypertension (an increase in blood pressure)
•
Nausea
•
Abdominal pain
•
Diarrhea
•
Constipation
•
Headache
•
Fever
•
Urinary tract infection


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•
Anemia
•
Thrombocytopenia
•
Arthralgia
•
Peeling of the skin over large areas of the body
•
Swelling just below the surface of the skin, most often around the lips and eyes
•
Hypersensitivity
Other side effects that are less common (3% to less than 20%): 
•
Sepsis
•
Pneumonia (lung infection)
•
Pyelonephritis (kidney infection)
•
Virus infection (herpes zoster, herpes simplex)
•
Venous thromboembolism (pulmonary embolism, deep venous thrombosis)
•
Tachycardia
•
Stomatitis
•
Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome
•
Hemolytic uremic syndrome (a kidney condition where destroyed red blood cells
block kidney filtering abilities.
•
Leukopenia
•
Abnormal healing
•
Increased lactic dehydrogenase (LDH)
•
Hypokalemia
•
Bone necrosis
•
Epistaxis (nose bleed)
•
Skin cancers (including melanoma, squamous cell carcinoma, and basal cell
carcinoma)
Other side effects that are possible, some may be serious include: 
•
Hepatotoxicity (liver dysfunction), including fatal hepatic necrosis, with elevated
Sirolimus trough concentrations
•
Pericardial effusion (fluid around the heart that may require an intervention)
•
Progressive multifocal leukoencephalopathy (PML)
•
Lung disease (including pulmonary fibrosis and pulmonary hemorrhage)
•
Nephrotic syndrome and kidney dysfunction
•
Azoospermia (lack of sperm production) which is reversible after discontinuation
of Sirolimus
Taking Sirolimus together with other medications that can cause liver function 
abnormalities may further increase the risk of severe liver injury.   


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Study Drugs 
9.6 
Drug Descriptions 
9.6.1 Turalio® Description 
Turalio®will be supplied in 200mg capsules and should be taken twice daily as split doses 
approximately 12 hours apart. Each dose should be taken with approximately 8 ounces of 
water. Subject should fast for at least two hours before and one hour after dosage. Each 
cycle of treatment will last 28 days. Turalio® should not be taken with medications that 
may decrease the acid content of the stomach as it may affect drug absorption.  
The dose level for the phase 2 portion of the study was determined to be dose level 3 
(Turalio® should be taken 400mg orally in AM and 600mg in PM daily in combination 
with Sirolimus 2mg orally daily in AM in a fasting state).  
Sirolimus Description 
Sirolimus will be supplied in 0.5mg, 1.0mg, or 2.0mg tablets and should be taken once 
daily (in AM) approximately 24 hours apart. Each dose should be taken with approximately 
8 ounces of water when taking the AM dose of Turalio®. Subject should fast for at least 
two hours before and one hour after dosage. Each cycle of treatment will last 28 days.  
9.7 
Treatment Regimen 
Turalio® and Sirolimus are oral tablets and are intended for continuous outpatient administration 
in 28 day cycles until criteria for ending the study have been met. Both drugs are to be taken two 
hours before or after a meal or snack. 
Turalio® is to be taken twice daily. Sirolimus is to be taken once daily. The drugs can be taken at 
the same time. Dose levels tested in the phase 1 portion of the study are indicated in Table 1, 
Section 5.1. 
The phase 1 study was executed as an open-label, continual reassessment method dosing of 
Turalio® and Sirolimus which began enrollment with a Turalio® dose of 800 mg per day, i.e., 400 
mg PO AM and 400mg PO PM along with Sirolimus 2mg PO daily in AM. Dose escalation groups 
were as described in Section 4.1.  
Review of the phase 1 safety data was assessed by the continual reassessment method and 
identified dose level 3 (Turalio® 1000mg in combination with Sirolimus 2mg) to be the 
recommended phase 2 dose. For dose modification guidelines for the phase 2 portion of the study, 
please refer to section 8.2 and Tables 10 – 14 above. 


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11.
MEASUREMENT OF EFFECT
11.1 
Antitumor Effect – Solid Tumors 
For the purposes of this study, patients should be re-evaluated for response every six weeks within 
the first 36 weeks.  In addition to a baseline scan, confirmatory scans should also be obtained six 
weeks following initial documentation of objective response. 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes 
are used in the RECIST criteria. Therapy may be permitted beyond progression if patient is 
deriving clinical benefit after initial tumor growth or ambiguity regarding the existence of disease 
progression in consultation with the principle investigator, sponsor, and central IRB. If subsequent 
imaging confirms tumor growth, progression will be back dated to the prior scan. If patient agrees 
to treatment beyond progression, the patient will be required to sign a “Treatment Beyond 
Progression” informed consent form. 
11.1.1 Definitions 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
treatment with Turalio® and Sirolimus. 
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that 
are evaluable but do not meet the definitions of measurable disease, have received at least 
one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for 
non-target disease.  The response assessment is based on the presence, absence, or 
unequivocal progression of the lesions. 


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11.2 
Disease Parameters 
Measurable disease: Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal 
lesions) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical 
exam.  All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  If the investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured 
and followed. 
Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target lesions. 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements.  It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected.  A sum of the diameters 


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(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, then 
only the short axis is added into the sum.  The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease. 
Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be recorded 
at baseline.  Measurements of these lesions are not required, but the presence, absence, or in rare 
cases unequivocal progression of each should be noted throughout follow-up.  
11.3 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  MRI is 
also acceptable in certain situations (e.g., for body scans).   
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement.  Furthermore, the availability of MRI is variable 
globally.  As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease.  Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence.  It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans.  Body scans should be performed 
with breath-hold scanning techniques, if possible. 


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PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed.   
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
Endoscopy/Laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised.  However, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J Clin 
Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the Gynecologic 
Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with 
objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
Cytology/Histology: These techniques can be used to differentiate between partial responses (PR) 
and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell 
tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible 'new' disease).  New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:  
•
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based
on a new lesion.


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•
No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET at
follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the positive FDG-
PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans
are needed to determine if there is truly progression occurring at that site (if so, the date of PD will
be the date of the initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up
corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the
anatomic images, this is not PD.
•
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases
where a residual radiographic abnormality is thought to represent fibrosis or scarring.  The use of
FDG-PET in this circumstance should be prospectively described in the protocol and supported by
disease-specific medical literature for the indication.  However, it must be acknowledged that both
approaches may lead to false positive CR due to limitations of FDG-PET and biopsy
resolution/sensitivity.
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
11.4 
Response Criteria 
11.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study).  In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one or 
more new lesions is also considered progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters while on study. 
11.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions. and normalization of 
tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm short 
axis). 
Note:  If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response. 


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Non-CR/Non-PD: Persistence of one or more non-target lesion(s). and/or maintenance of 
tumor marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally 
trump target lesion status.  It must be representative of overall disease status change, not 
a single lesion increase. Although a clear progression of “non-target” lesions only is 
exceptional, the opinion of the treating physician should prevail in such circumstances, 
and the progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
11.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response 
assignment will depend on the achievement of both measurement and confirmation 
criteria. 
Response classification for Patients with Measurable Disease (e.g., Target Disease) 
Target Lesions 
Non-Target Lesions New 
Lesions 
Overall 
Response 
Best 
Overall 
Response 
when 
Confirmation 
is 
Required* 
CR 
CR 
No 
CR 
8 weeks 
CR 
Non-CR/Non-PD 
No 
PR 
8 weeks 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
8 weeks 
PD 
Any 
Yes 
or 
No 
PD 
no prior SD, PR or CR 
Any 
PD** 
Yes 
or 
No 
PD 
Any 
Any 
Yes 
PD 
*
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
**       In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
For Patients with Non-Measurable Disease (e.g., Non-Target Disease) 


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Non-Target Lesions New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this
category when no lesions can be measured is not advised
11.5 
Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
11.6 
Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 


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13. 
STATISTICAL CONSIDERATIONS
13.1 
Study Design/Endpoints 
For study design and statistical consideration, please refer to section 5.1. 
Phase 1 study Primary aim: 
To determine the recommended phase 2 dose (RP2D) and safety for Turalio® when administered 
orally in combination with Sirolimus in patients with unresectable or metastatic sarcoma.  A 
total of 18 evaluable unresectable or metastatic sarcoma patients were enrolled.  
Phase 2 study primary aim: 
To determine the preliminary efficacy of Turalio® in combination with Sirolimus in patients with 
unresectable or metastatic MPNST by determining the median progression free survival. 
The primary endpoint is progression free survival (PFS), which is defined as the time from the 
start of the treatment until disease progression or death from any cause. Assuming a median PFS 
of 6 weeks in patients treated with standard of care (23) with a sample size of 25, we have 90% 
power to detect a difference of 12 weeks in median PFS (6 weeks versus 18weeks) given a 2-
sided test with an alpha of 0.05. Thus, a total of 25 evaluable unresectable or metastatic MPNST 
patients will be enrolled. 
Phase 2 study Secondary aims: 
To investigate the objective response rate (ORR) and overall survival (OS) of Turalio® in 
combination with Sirolimus in patients with unresectable malignant peripheral nerve sheath 
tumors (MPNSTs). 


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13.3 Analysis of Primary and Secondary Endpoints and Evaluation of Tissue 
13.3.1 Primary Analysis 
Phase I:  The MTD will be estimated using the Continual Reassessment Method. The proportion 
of DLT at each dose level will be reported along with the final estimates of the probability of 
DLT based on the TTE-CRM.   
Phase II:  Progression free survival will be estimated using the Kaplan Meier method. Median 
PFS and 95% confidence intervals will be reported.  
Secondary analysis: 
Overall survival, defined as the time from the start of treatment until death, will be estimated using 
the Kaplan Meier method. Median OS and 95% confidence intervals will be reported.  
Best response rate at weeks will be reported as a proportion along with the exact 95% confidence 
interval.   


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