Malignant Peripheral Nerve Sheath Tumors (MPNST), Sarcoma
Conditions
Keywords
Malignant Peripheral Nerve Sheath Tumors, MPNST, Sarcoma, Ganetespib, Sirolimus, mTOR inhibitor, Heat shock protein, Hsp90
Brief summary
Phase 1: To assess the safety, tolerability, and maximum tolerated dose (MTD)/ recommended dose of ganetespib when administered in combination with sirolimus in patients with refractory or relapsed sarcomas including unresectable or metastatic sporadic or neurofibromatosis type 1 (NF1) associated MPNST. Phase I enrollment has been closed. Phase 2: To determine the clinical benefit of ganetespib in combination with sirolimus for patients with unresectable or metastatic sporadic or NF1 associated MPNST.
Detailed description
Previously, no targeted agents have been able to cause tumor regression in a genetically engineered MPNST mouse model or human MPNST. Recently published data from Dr. Cichowski's laboratory demonstrated using Hsp90 inhibitors to enhance endoplasmic reticulum stress coupled with the mammalian target of rapamycin (mTOR) inhibitor sirolimus led to dramatic tumor shrinkage in a transgenic MPNST mouse model, which correlated with profound damage to the endoplasmic reticulum and cell death. Ganetespib is a novel, injectable, small molecule inhibitor of Hsp90 and is currently being investigated in adults with a broad range of tumor types with a favorable safety profile and promising early results. Ganetespib has been studied in preclinical in vivo models with a variety of targeted agents with no marked apparent pharmacological interactions. Sirolimus is a commercially available orally administered mTOR inhibitor and is the active metabolite of temsirolimus, which is FDA approved agent for advanced metastatic renal cell carcinoma. Sirolimus has been studied and tolerated in combination with multiple cytotoxic and targeted agents in a variety of tumor types. Based on strong preclinical rationale, the investigators hypothesize that ganetespib in combination with sirolimus will cause tumor regression in patients with refractory MPNSTs. The investigators propose a multi-institutional open label phase I/II trial of ganetespib in combination with sirolimus in patients with refractory sarcoma including MPNST. Hsp90 inhibitors and mTOR inhibitors have also both demonstrated benefit in a variety of preclinical bone and soft tissue sarcoma models. The investigators hypothesize that these agents that work on separate and potentially synergistic pathways will also be beneficial for other refractory bone and soft tissue sarcomas. Thus, the phase I component will be open to patients with refractory sarcomas, which will also expedite enrollment. Upon determination of the recommended dosing, a phase II study will be conducted. The phase II study population will be limited to patients with a diagnosis of MPNST.
Interventions
DRUGganetespib
Phase 1 Dose 1: 150 mg/m² IV on days 1, 8, and 15 intravenously over 1 hour; Phase 1 Dose 2: 200 mg/m² IV on days 1, 8, and 15 intravenously over 1 hour; Phase 2: 200 mg/m² IV on days 1, 8, and 15 intravenously over 1 hour
DRUGSirolimus
4mg taken orally once daily on a continuous dosing schedule; Loading dose 12 mg on cycle 1 day 1 only.
Sponsors
Synta Pharmaceuticals Corp.
United States Department of Defense
Sarcoma Alliance for Research through Collaboration
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients ≥ 16 years old * Patients with unresectable or metastatic histologically confirmed sporadic or NF1 associated high grade MPNST * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 * Patients must have at least 1 measurable tumor * Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy (toxicity \< grade 2) * Must be able to swallow whole pills * Adequate organ function * Normal fasting cholesterol and triglycerides * May be on cholesterol medications
Exclusion criteria
* Patients receiving current treatment with corticosteroids or another immunosuppressive. Topical or inhaled corticosteroids are allowed. * Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases * Symptomatic congestive heart failure * Severely impaired lung function * Significant vascular disease * Uncontrolled diabetes * Active (acute or chronic) or uncontrolled severe infections hepatitis * Impairment of gastrointestinal function * Patients with an active, bleeding diathesis or significant coagulopathy * Use of cytochrome P450 isoenzyme 3A4 (CYP3A4)/ CYP2C19 substrates
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Dose Limiting Toxicities of Ganetespib When Administered in Combination With Sirolimus. | Toxicities will be evaluated over the first treatment cycle (each cycle=28 days) | To assess the safety, tolerability, and maximum tolerated/ recommended dose of ganetespib when administered in combination with sirolimus in patients with refractory sarcomas or unresectable or metastatic sporadic or neurofibromatosis type 1 (NF1) associated MPNST. Toxicities observed during the first cycle will be used to define the MTD/Recommended dose. Toxicity will be graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. DLT will be defined as any of the following events that are possibly, probably, or definitely attributable to ganetespib or sirolimus. The DLT observation period for the purposes of dose escalation will be the first cycle of therapy. |
| Clinical Benefit of Ganetespib in Combination With Sirolimus | Response evaluations will be performed after every 2 treatment cycles (each cycle=28 days) | Assessed using the World Health Organization (WHO) criteria. Tumor assessments will be obtained every 2 cycles. Clinical benefit is defined as stable disease, Partial Response (PR), Complete Response (CR). For patients who experience progression by WHO but in the opinion of the treating investigator are deriving benefit from therapy and have not otherwise met off treatment or off study criteria, may continue on treatment as long as patient has not met progression by RECIST 1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patient-reported Pain Severity and the Impact of Pain on Daily Activities | Baseline and prior to Cycle 3 | To assess patient-reported pain severity and the impact of pain on daily activities before and during treatment with ganetespib and sirolimus. The Numerical Rating Scale-11 (NRS-11) will be used to assess pain severity. The NRS-11 is a self-report segmented 11-point numeric scale that assesses pain severity. It consists of a horizontal line with 0 representing no pain at the right end of the line and 10 representing worst pain you can imagine at the left end.The Brief Pain Inventory is a 7-item self-report questionnaire that measures the extent to which pain interferes with daily functioning. Patients are asked to indicate how much pain interfered with various activities in the past week, with scores ranging from 0 (does not interfere) to 10 (completely interferes). A total score is obtained by taking the mean of the scores for all 7 items; thus, the total pain interference score can range from 0 to 10. |
| Utility of Three-dimensional MRI (3D-MRI) Analysis in Comparison to 1-dimensional and 2-dimensional Measurements | 4 months | To evaluate the utility of three-dimensional MRI (3D-MRI) analysis in comparison to 1-dimensional and 2-dimensional measurements as a method to more sensitively monitor response. |
| Change in Plasma Pharmacokinetic Profile of Ganetespib and Sirolimus When Administered in Combination-Observed Maximum Plasma Concentration (Cmax) | Pre-therapy levels drawn at baseline and pharmacokinetic analysis occurs on Cycle 1 Day 15 | To describe the plasma pharmacokinetic profile of ganetespib and sirolimus when administered in combination therapy. |
| Determine Maximum Tolerated Dose (MTD)/Recommended Dose (RD) of Ganetespib | Phase 1 of study | A conventional 3+3 dose escalation design was used for phase 1. All patients in phase 2 were treated with the recommended dose. |
| Plasma Pharmacokinetic Profile of Ganetespib When Administered in Combination With Sirolimus | Cycle 1 Day 15 | To describe the plasma pharmacokinetic profile of ganetespib in terms of half life. |
| Changes in Pharmacodynamic Parameters in Peripheral Blood Mononuclear Cells | Baseline and Cycle 1 Day 15 | To explore changes in pharmacodynamic parameters in peripheral blood mononuclear cells performed on day 1 prior to ganetespib and sirolimus administration, and on day 15, 6 hours post drug administration. Hsp inhibition (Hsp70), mTOR inhibition (phospho-S6 and Akt Phosphorylation), UPR activation (EIF2alpha phosphorylation) will be explored. Western blot analyses were performed for phospho (p)-Akt, p-eIF2α, p-S6, and Hsp70. The absorbance of each phosphoprotein lane was recorded and protein levels were determined after normalizing for levels of corresponding total protein. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ganetespib / Sirolimus 28-day cycles of ganetespib + sirolimus
ganetespib: 200 mg/m² IV on days 1, 8, and 15 intravenously over 1 hour
Sirolimus: 2mg taken orally once daily on a continuous dosing schedule; Loading dose 12 mg on cycle 1 day 1 only. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Inevaluable | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Ganetespib / Sirolimus |
|---|---|
| Age, Continuous Phase 2 | 38 years |
| Age, Continuous Phase I | 26 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| History of metastatic disease Phase 1 | 9 Participants |
| History of metastatic disease Phase 2 | 9 Participants |
| Prior chemotherapy regimen Phase 1 | 10 Participants |
| Prior chemotherapy regimen Phase 2 | 8 Participants |
| Prior radiation Phase 1 | 7 Participants |
| Prior radiation Phase 2 | 6 Participants |
| Prior surgery Phase 1 | 10 Participants |
| Prior surgery Phase 2 | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 14 Participants |
| Sarcoma subtype Phase 2 Alveolar soft part sarcoma | 0 Participants |
| Sarcoma subtype Phase 2 Ewing sarcoma | 0 Participants |
| Sarcoma subtype Phase 2 Leiomyosarcoma | 0 Participants |
| Sarcoma subtype Phase 2 Liposarcoma | 0 Participants |
| Sarcoma subtype Phase 2 MPNST NF1 Associated | 5 Participants |
| Sarcoma subtype Phase 2 MPNST Sporadic | 5 Participants |
| Sarcoma subtype Phase I Alveolar soft part sarcoma | 1 Participants |
| Sarcoma subtype Phase I Ewing sarcoma | 1 Participants |
| Sarcoma subtype Phase I Leiomyosarcoma | 2 Participants |
| Sarcoma subtype Phase I Liposarcoma | 3 Participants |
| Sarcoma subtype Phase I MPNST NF1 Associated | 3 Participants |
| Sarcoma subtype Phase I MPNST Sporadic | 0 Participants |
| Sex: Female, Male Phase 2 Female | 4 Participants |
| Sex: Female, Male Phase 2 Male | 6 Participants |
| Sex: Female, Male Phase I Female | 2 Participants |
| Sex: Female, Male Phase I Male | 8 Participants |
| Tumor location at diagnosis Phase 2 Abdomen | 1 Participants |
| Tumor location at diagnosis Phase 2 Extremity | 4 Participants |
| Tumor location at diagnosis Phase 2 Head | 0 Participants |
| Tumor location at diagnosis Phase 2 Lung | 1 Participants |
| Tumor location at diagnosis Phase 2 Mediastinum | 0 Participants |
| Tumor location at diagnosis Phase 2 Other | 2 Participants |
| Tumor location at diagnosis Phase 2 Peritoneum | 0 Participants |
| Tumor location at diagnosis Phase 2 Skin | 0 Participants |
| Tumor location at diagnosis Phase 2 Spine | 2 Participants |
| Tumor location at diagnosis Phase I Abdomen | 1 Participants |
| Tumor location at diagnosis Phase I Extremity | 1 Participants |
| Tumor location at diagnosis Phase I Head | 1 Participants |
| Tumor location at diagnosis Phase I Lung | 0 Participants |
| Tumor location at diagnosis Phase I Mediastinum | 1 Participants |
| Tumor location at diagnosis Phase I Other | 3 Participants |
| Tumor location at diagnosis Phase I Peritoneum | 1 Participants |
| Tumor location at diagnosis Phase I Skin | 1 Participants |
| Tumor location at diagnosis Phase I Spine | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 1 / 7 | 1 / 10 |
| other Total, other adverse events | 3 / 3 | 7 / 7 | 10 / 10 |
| serious Total, serious adverse events | 1 / 3 | 2 / 7 | 6 / 10 |
Outcome results
Primary
Clinical Benefit of Ganetespib in Combination With Sirolimus
Assessed using the World Health Organization (WHO) criteria. Tumor assessments will be obtained every 2 cycles. Clinical benefit is defined as stable disease, Partial Response (PR), Complete Response (CR). For patients who experience progression by WHO but in the opinion of the treating investigator are deriving benefit from therapy and have not otherwise met off treatment or off study criteria, may continue on treatment as long as patient has not met progression by RECIST 1.1.
Time frame: Response evaluations will be performed after every 2 treatment cycles (each cycle=28 days)
Population: 10 patients were enrolled in Phase 1 and 10 patients were enrolled in Phase 2 of the study. Overall number of patients enrolled was 20.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ganetespib / Sirolimus | Clinical Benefit of Ganetespib in Combination With Sirolimus | Phase 1 | 1 Participants |
| Ganetespib / Sirolimus | Clinical Benefit of Ganetespib in Combination With Sirolimus | Phase 2 | 0 Participants |
Primary
Number of Dose Limiting Toxicities of Ganetespib When Administered in Combination With Sirolimus.
To assess the safety, tolerability, and maximum tolerated/ recommended dose of ganetespib when administered in combination with sirolimus in patients with refractory sarcomas or unresectable or metastatic sporadic or neurofibromatosis type 1 (NF1) associated MPNST. Toxicities observed during the first cycle will be used to define the MTD/Recommended dose. Toxicity will be graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. DLT will be defined as any of the following events that are possibly, probably, or definitely attributable to ganetespib or sirolimus. The DLT observation period for the purposes of dose escalation will be the first cycle of therapy.
Time frame: Toxicities will be evaluated over the first treatment cycle (each cycle=28 days)
Population: 10 patients were enrolled in Phase 1 of the study to determine MTD/RD. Three patients were enrolled in the first dose level. Six patients were enrolled at dose level 2. 1 patient was inevaluable.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ganetespib / Sirolimus | Number of Dose Limiting Toxicities of Ganetespib When Administered in Combination With Sirolimus. | Dose Level 1 | 0 DLTs |
| Ganetespib / Sirolimus | Number of Dose Limiting Toxicities of Ganetespib When Administered in Combination With Sirolimus. | Dose Level 2 | 1 DLTs |
Secondary
Change in Plasma Pharmacokinetic Profile of Ganetespib and Sirolimus When Administered in Combination-Observed Maximum Plasma Concentration (Cmax)
To describe the plasma pharmacokinetic profile of ganetespib and sirolimus when administered in combination therapy.
Time frame: Pre-therapy levels drawn at baseline and pharmacokinetic analysis occurs on Cycle 1 Day 15
Population: 10 patients were enrolled in Phase 1 of the study. Three patients were enrolled in the first dose level. Six patients were enrolled at dose level 2. 1 patient was inevaluable.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ganetespib / Sirolimus | Change in Plasma Pharmacokinetic Profile of Ganetespib and Sirolimus When Administered in Combination-Observed Maximum Plasma Concentration (Cmax) | Dose Level 1- Sirolimus trough | 12.1 ng/mL | Standard Deviation 3.6 |
| Ganetespib / Sirolimus | Change in Plasma Pharmacokinetic Profile of Ganetespib and Sirolimus When Administered in Combination-Observed Maximum Plasma Concentration (Cmax) | Dose Level 2- Sirolimus trough | 12.5 ng/mL | Standard Deviation 8.9 |
Secondary
Changes in Pharmacodynamic Parameters in Peripheral Blood Mononuclear Cells
To explore changes in pharmacodynamic parameters in peripheral blood mononuclear cells performed on day 1 prior to ganetespib and sirolimus administration, and on day 15, 6 hours post drug administration. Hsp inhibition (Hsp70), mTOR inhibition (phospho-S6 and Akt Phosphorylation), UPR activation (EIF2alpha phosphorylation) will be explored. Western blot analyses were performed for phospho (p)-Akt, p-eIF2α, p-S6, and Hsp70. The absorbance of each phosphoprotein lane was recorded and protein levels were determined after normalizing for levels of corresponding total protein.
Time frame: Baseline and Cycle 1 Day 15
Population: 11 subjects provided consent and had adequate specimens for analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ganetespib / Sirolimus | Changes in Pharmacodynamic Parameters in Peripheral Blood Mononuclear Cells | Hsp70 at Baseline | 0.81 ratio | Standard Deviation 0.39 |
| Ganetespib / Sirolimus | Changes in Pharmacodynamic Parameters in Peripheral Blood Mononuclear Cells | Hsp70 at Cycle 1 Day 15 | 0.84 ratio | Standard Deviation 0.56 |
| Ganetespib / Sirolimus | Changes in Pharmacodynamic Parameters in Peripheral Blood Mononuclear Cells | pAKT at Baseline | 1.20 ratio | Standard Deviation 0.7 |
| Ganetespib / Sirolimus | Changes in Pharmacodynamic Parameters in Peripheral Blood Mononuclear Cells | pAKT at Cycle 1 Day 15 | 1.44 ratio | Standard Deviation 1 |
| Ganetespib / Sirolimus | Changes in Pharmacodynamic Parameters in Peripheral Blood Mononuclear Cells | p-S6 at Baseline | 1.25 ratio | Standard Deviation 0.4 |
| Ganetespib / Sirolimus | Changes in Pharmacodynamic Parameters in Peripheral Blood Mononuclear Cells | p-S6 at Cycle 1 Day 15 | 0.54 ratio | Standard Deviation 0.24 |
| Ganetespib / Sirolimus | Changes in Pharmacodynamic Parameters in Peripheral Blood Mononuclear Cells | p-eiF2alpha at Baseline | 1.02 ratio | Standard Deviation 0.26 |
| Ganetespib / Sirolimus | Changes in Pharmacodynamic Parameters in Peripheral Blood Mononuclear Cells | p-eiF2alpha at Cycle 1 Day 15 | 0.49 ratio | Standard Deviation 0.22 |
Secondary
Determine Maximum Tolerated Dose (MTD)/Recommended Dose (RD) of Ganetespib
A conventional 3+3 dose escalation design was used for phase 1. All patients in phase 2 were treated with the recommended dose.
Time frame: Phase 1 of study
Population: 1 patient was inevaluable in Phase 1 of study. The recommended dose of ganetespib was determined to be 200 mg/m2 intravenously on days 1, 8, 15 with sirolimus 4mg orally once daily with a cycle 1 day 1 loading dose of 12mg. All patients in phase 2 were treated with the recommended dose.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ganetespib / Sirolimus | Determine Maximum Tolerated Dose (MTD)/Recommended Dose (RD) of Ganetespib | 3 Participants |
| Phase 1 Dose Level 2 | Determine Maximum Tolerated Dose (MTD)/Recommended Dose (RD) of Ganetespib | 6 Participants |
| Phase 2 | Determine Maximum Tolerated Dose (MTD)/Recommended Dose (RD) of Ganetespib | 10 Participants |
Secondary
Patient-reported Pain Severity and the Impact of Pain on Daily Activities
To assess patient-reported pain severity and the impact of pain on daily activities before and during treatment with ganetespib and sirolimus. The Numerical Rating Scale-11 (NRS-11) will be used to assess pain severity. The NRS-11 is a self-report segmented 11-point numeric scale that assesses pain severity. It consists of a horizontal line with 0 representing no pain at the right end of the line and 10 representing worst pain you can imagine at the left end.The Brief Pain Inventory is a 7-item self-report questionnaire that measures the extent to which pain interferes with daily functioning. Patients are asked to indicate how much pain interfered with various activities in the past week, with scores ranging from 0 (does not interfere) to 10 (completely interferes). A total score is obtained by taking the mean of the scores for all 7 items; thus, the total pain interference score can range from 0 to 10.
Time frame: Baseline and prior to Cycle 3
Population: Thirteen subjects in phase 1 and phase 2 cohorts combined had MPNST and completed the pain evaluations. 4/13 subjects completed both baseline and pre-cycle 3 evaluations for pain.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Ganetespib / Sirolimus | Patient-reported Pain Severity and the Impact of Pain on Daily Activities | Baseline- Overall pain intensity | 7.5 units on a scale |
| Ganetespib / Sirolimus | Patient-reported Pain Severity and the Impact of Pain on Daily Activities | Baseline- Tumor pain intensity | 7.5 units on a scale |
| Ganetespib / Sirolimus | Patient-reported Pain Severity and the Impact of Pain on Daily Activities | Baseline- Pain interference | 6.49 units on a scale |
| Ganetespib / Sirolimus | Patient-reported Pain Severity and the Impact of Pain on Daily Activities | Prior to Cycle 3- Overall pain intensity | 5 units on a scale |
| Ganetespib / Sirolimus | Patient-reported Pain Severity and the Impact of Pain on Daily Activities | Prior to Cycle 3- Tumor pain intensity | 4.75 units on a scale |
| Ganetespib / Sirolimus | Patient-reported Pain Severity and the Impact of Pain on Daily Activities | Prior to Cycle 3- Pain interference | 3.14 units on a scale |
Secondary
Plasma Pharmacokinetic Profile of Ganetespib When Administered in Combination With Sirolimus
To describe the plasma pharmacokinetic profile of ganetespib in terms of half life.
Time frame: Cycle 1 Day 15
Population: 10 patients were enrolled in Phase 1 of the study. 1 patient was inevaluable.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ganetespib / Sirolimus | Plasma Pharmacokinetic Profile of Ganetespib When Administered in Combination With Sirolimus | Ganetespib half life for dose level 1 | 6.4 hours | Standard Deviation 2.1 |
| Ganetespib / Sirolimus | Plasma Pharmacokinetic Profile of Ganetespib When Administered in Combination With Sirolimus | Ganetespib half life for dose level 2 | 6.0 hours | Standard Deviation 0.9 |
Secondary
Utility of Three-dimensional MRI (3D-MRI) Analysis in Comparison to 1-dimensional and 2-dimensional Measurements
To evaluate the utility of three-dimensional MRI (3D-MRI) analysis in comparison to 1-dimensional and 2-dimensional measurements as a method to more sensitively monitor response.
Time frame: 4 months
Population: The 3D-MRI were not measurable with current modalities. Due to their nature and incomplete imaging, volumetric analysis was not feasible.