A Phase 1/2 interventional study of ganetespib and Sirolimus in Malignant Peripheral Nerve Sheath Tumors (MPNST) and Sarcoma, sponsored by Sarcoma Alliance for Research through Collaboration. Completed at 7 sites in United States. Open to participants aged 16 Years and older. Per ClinicalTrials.gov, last updated 2019-05-15.
Sponsored by Sarcoma Alliance for Research through Collaboration · Phase 1/2, Interventional, and Treatment
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.
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.
71 studies on the registry are indexed under Neurofibrosarcoma; 22 are open to participants now.
This study's enrollment of 20 is below the median of 44 across 59 interventional studies indexed under Neurofibrosarcoma.
Browse Neurofibrosarcoma studies →Sarcoma Alliance for Research through Collaboration is the lead sponsor of 23 studies on the registry; 2 are open to participants now.
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Exclusion Criteria:
28-day cycles of ganetespib + sirolimus
Drug: ganetespib · Drug: Sirolimus
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
Also known as: STA-9090
4mg taken orally once daily on a continuous dosing schedule; Loading dose 12 mg on cycle 1 day 1 only.
Also known as: Rapamycin
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)
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)
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
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
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
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
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
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
| Milestone | Phase 1 Dose 1 | Phase 1 Dose 2 | Phase 2 |
|---|---|---|---|
| Started | 3 | 7 | 10 |
| Completed | 3 | 6 | 10 |
| Not completed | 0 | 1 | 0 |
| Withdrew: Inevaluable | 0 | 1 | 0 |
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.
| DLTs | Ganetespib / Sirolimus |
|---|---|
| Dose Level 1 | 0 |
| Dose Level 2 | 1 |
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.
| Participants | Ganetespib / Sirolimus |
|---|---|
| Phase 1 | 1 |
| Phase 2 | 0 |
To describe the plasma pharmacokinetic profile of ganetespib and sirolimus when administered in combination therapy.
| ng/mL | Ganetespib / Sirolimus |
|---|---|
| Dose Level 1- Sirolimus trough | 12.1 ± 3.6 |
| Dose Level 2- Sirolimus trough | 12.5 ± 8.9 |
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.
| ratio | Ganetespib / Sirolimus |
|---|---|
| Hsp70 at Baseline | 0.81 ± 0.39 |
| Hsp70 at Cycle 1 Day 15 | 0.84 ± 0.56 |
| pAKT at Baseline | 1.20 ± 0.70 |
| pAKT at Cycle 1 Day 15 | 1.44 ± 1.00 |
| p-S6 at Baseline | 1.25 ± 0.40 |
| p-S6 at Cycle 1 Day 15 | 0.54 ± 0.24 |
| p-eiF2alpha at Baseline | 1.02 ± 0.26 |
| p-eiF2alpha at Cycle 1 Day 15 | 0.49 ± 0.22 |
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.
| units on a scale | Ganetespib / Sirolimus |
|---|---|
| Baseline- Overall pain intensity | 7.5 (0 to 10) |
| Baseline- Tumor pain intensity | 7.5 (0 to 10) |
| Baseline- Pain interference | 6.49 (0 to 10) |
| Prior to Cycle 3- Overall pain intensity | 5 (0 to 10) |
| Prior to Cycle 3- Tumor pain intensity | 4.75 (0 to 10) |
| Prior to Cycle 3- Pain interference | 3.14 (0 to 10) |
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.
No measurements were reported for this outcome.
To describe the plasma pharmacokinetic profile of ganetespib in terms of half life.
| hours | Ganetespib / Sirolimus |
|---|---|
| Ganetespib half life for dose level 1 | 6.4 ± 2.1 |
| Ganetespib half life for dose level 2 | 6.0 ± 0.9 |
A conventional 3+3 dose escalation design was used for phase 1. All patients in phase 2 were treated with the recommended dose.
| Participants | Phase 1 Dose Level 1 | Phase 1 Dose Level 2 | Phase 2 |
|---|---|---|---|
| Determine Maximum Tolerated Dose (MTD)/Recommended Dose (RD) of Ganetespib | 3 | 6 | 10 |
Collected over 3 years. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Phase 1 Dose 1 | 0/3 (0%) | 1/3 (33.3%) | 3/3 (100%) |
| Phase 1 Dose 2 | 1/7 (14.3%) | 2/7 (28.6%) | 7/7 (100%) |
| Phase 2 | 1/10 (10%) | 6/10 (60%) | 10/10 (100%) |
| Event | Phase 1 Dose 1 | Phase 1 Dose 2 | Phase 2 |
|---|---|---|---|
| DyspneaRespiratory, thoracic and mediastinal disorders | 1/3 | 0/7 | 0/10 |
| HypoglycemiaMetabolism and nutrition disorders | 1/3 | 0/7 | 0/10 |
| CholecystitisHepatobiliary disorders | 0/3 | 1/7 | 1/10 |
| FeverGeneral disorders | 0/3 | 1/7 | 0/10 |
| Infusion related reactionGeneral disorders | 0/3 | 1/7 | 0/10 |
| Gastrointestinal disorders- otherGastrointestinal disorders | 0/3 | 0/7 | 1/10 |
| Alanine Aminotransferase increasedInvestigations | 0/3 | 0/7 | 1/10 |
| Aspartate Aminotransferase increasedInvestigations | 0/3 | 0/7 | 1/10 |
| DehydrationMetabolism and nutrition disorders | 0/3 | 0/7 | 1/10 |
| DiarrheaGastrointestinal disorders | 0/3 | 0/7 | 1/10 |
| Event | Phase 1 Dose 1 | Phase 1 Dose 2 | Phase 2 |
|---|---|---|---|
| DiarrheaGastrointestinal disorders | 2/3 | 7/7 | 8/10 |
| NauseaGastrointestinal disorders | 1/3 | 3/7 | 7/10 |
| AnorexiaMetabolism and nutrition disorders | 2/3 | 0/7 | 1/10 |
| Aspartate Aminotransferase increasedInvestigations | 2/3 | 1/7 | 3/10 |
| CoughRespiratory, thoracic and mediastinal disorders | 2/3 | 0/7 | 1/10 |
| FatigueGeneral disorders | 2/3 | 1/7 | 6/10 |
| HeadacheNervous system disorders | 2/3 | 3/7 | 0/10 |
| HyperglycemiaMetabolism and nutrition disorders | 2/3 | 2/7 | 2/10 |
| HypophosphatemiaMetabolism and nutrition disorders | 2/3 | 1/7 | 1/10 |
| Lymphocyte count decreasedInvestigations | 2/3 | 3/7 | 4/10 |
| Age, Continuous(years) | Ganetespib / Sirolimus |
|---|---|
| Phase I | 26 (16 to 89) |
| Phase 2 | 38 (24 to 61) |
| Sex: Female, Male(Participants) | Ganetespib / Sirolimus |
|---|---|
| Phase I — Female | 2 |
| Phase I — Male | 8 |
| Phase 2 — Female | 4 |
| Phase 2 — Male | 6 |
| Ethnicity (NIH/OMB)(Participants) | Ganetespib / Sirolimus |
|---|---|
| Hispanic or Latino | 4 |
| Not Hispanic or Latino | 16 |
| Unknown or Not Reported | 0 |
| Race (NIH/OMB)(Participants) | Ganetespib / Sirolimus |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 2 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 2 |
| White | 14 |
| More than one race | 0 |
| Unknown or Not Reported | 2 |
| Sarcoma subtype(Participants) | Ganetespib / Sirolimus |
|---|---|
| Phase I — Alveolar soft part sarcoma | 1 |
| Phase I — Ewing sarcoma | 1 |
| Phase I — Leiomyosarcoma | 2 |
| Phase I — Liposarcoma | 3 |
| Phase I — MPNST NF1 Associated | 3 |
| Phase I — MPNST Sporadic | 0 |
| Phase 2 — Alveolar soft part sarcoma | 0 |
| Phase 2 — Ewing sarcoma | 0 |
| Phase 2 — Leiomyosarcoma | 0 |
| Phase 2 — Liposarcoma | 0 |
| Phase 2 — MPNST NF1 Associated | 5 |
| Phase 2 — MPNST Sporadic | 5 |
| Tumor location at diagnosis(Participants) | Ganetespib / Sirolimus |
|---|---|
| Phase I — Abdomen | 1 |
| Phase I — Extremity | 1 |
| Phase I — Head | 1 |
| Phase I — Lung | 0 |
| Phase I — Mediastinum | 1 |
| Phase I — Peritoneum | 1 |
| Phase I — Skin | 1 |
| Phase I — Spine | 1 |
| Phase I — Other | 3 |
| Phase 2 — Abdomen | 1 |
| Phase 2 — Extremity | 4 |
| Phase 2 — Head | 0 |
| Phase 2 — Lung | 1 |
| Phase 2 — Mediastinum | 0 |
| Phase 2 — Peritoneum | 0 |
| Phase 2 — Skin | 0 |
| Phase 2 — Spine | 2 |
| Phase 2 — Other | 2 |
| History of metastatic disease(Participants) | Ganetespib / Sirolimus |
|---|---|
| Phase 1 | 9 |
| Phase 2 | 9 |
| Prior chemotherapy regimen(Participants) | Ganetespib / Sirolimus |
|---|---|
| Phase 1 | 10 |
| Phase 2 | 8 |
2 further baseline measures are reported on the registry.
Documents are hosted by the registry — open the source record to download them.
The record gives a start of Dec 2013, a primary completion of Apr 2018 and a completion of Jul 2018. It does not say whether these dates are actual or estimated.
Results were first posted in May 2019, 1 year 1 month after primary completion.
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This study is completed, as verified in Apr 2019. You cannot join it, but the record below documents what was studied.
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Studies of the drugs tested here: STA 9090 · Sirolimus
Sarcoma Alliance for Research through Collaboration