Symptoms and General Pathology

All Conditions

Neoplasms

Skin and Connective Tissue Diseases

Shock

Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Bevacizumab

Hormones

Estrogens

89Zr-bevacizumab

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Radiopharmaceuticals

Patients with estrogen receptor (ER) positive, hormone therapy refractory breast cancer.

injection 89Zr-bevacizumab and 89 Zr-bevacizumab PET scan

89Zr-bevacizumab PET imaging

C.P. Schröder, PhD

Inhibition of Heat Shock Protein (HSP)90 is a new, promising treatment modality for cancer patients, particularly in the setting of resistance. A reliable read out system (biomarker) for the evaluation of early treatment effect is of great importance in the development of this treatment modality, and could contribute to customize this treatment for individual patients. So far, no reliable biomarker has been described for HSP90 effect. Visualizing the effect of HSP90 on vascular endothelial growth factor (VEGF) secretion in vivo in the patient, by whole body 89Zr-bevacizumab uptake, can be of great importance in this respect, and may contribute to tailored made cancer treatment. The purpose of the present study is to evaluate the effect of HSP90 inhibition by AUY922 on VEGF by means of 89ZR-bevacizumab PET.

This feasibility study is designed as a side study to the multicenter, international phase I-II trial with HSP90 inhibitor AUY922 (protocol CAUY922A2101), as part of the biomarker assessment. In protocol CAUY922A2101, section 4, the design of this phase I-II trial is described (p37, 38). Briefly, a dose-escalation study is performed according to phase I design in adult patients with advanced solid malignancies. This part is followed by a dose-expansion study according to a phase II design. In the latter part, breast cancer patients are enrolled that are either refractory to hormone- or trastuzumab treatment (both treatment arms, n=40 patients), on the maximal tolerated dose of AUY922 based on the phase I part of the study. Patients with ER positive, hormone therapy refractory breast cancer, will receive a 89Zr-bevacizumab PET scan as part of the present side study protocol, which will be performed in collaboration with the Royal Marsden Hospital (United Kingdom).

To this end, a 89Zr-bevacizumab PET scan will be performed before (baseline) and during treatment with HSP90 inhibitor AUY922, as described below.

A minimum of six patients will be entered to evaluate whether the effect of HSP90 inhibition by AUY922 can be detected with a 89Zr-bevacizumab PET scan

Imaging HSP90 Inhibitor AUY922 on VEGF-89ZR-bevacizumab Positron Emission Tomography (PET)

Imaging the Effect of HSP90 Inhibitor AUY922 on VEGF by Means of 89Zr-bevacizumab PET

Primary endpoint: measurement of decreased VEGF compared to baseline. A decline is defined as a decrease of at least 30% in mean Standardized Uptake Value (SUV) in a maximum of three lesions.

University Medical Center Groningen

Diarrhea

Signs and Symptoms, Digestive

Amino Acids

Irinotecan

Fluorouracil

Glutamine

Glutamine 10 g four times daily starting two days before treatment for six days in total

Placebo

Michael Sawyer, MD

Irinotecan (7-ethyl-10- {4(-1-piperidino)-1-piperidino} carbonyloxy camptothecin) is a semisynthetic camptothecin derivative introduced in the 1980's. Irinotecan is a prodrug metabolized by carboxylesterases to an active metabolite 7-ethyl-10-hydroxy-camptothecin (SN38). SN38 exerts its cytotoxic effect by forming stable complexes with topoisomerase I and DNA. These complexes collide with replication forks and cause breaks in DNA. Studies substantiated irinotecan's activity in 5FU resistant colorectal cancer and led to its approval for treatment of 5FU resistant colorectal cancer in the United States, Canada and Europe.Colorectal cancer studies demonstrated that single agent irinotecan's dose limiting toxicity was diarrhea occurring 5 to 6 days after its administration. High dose loperamide at first occurrence of diarrhea has decreased the incidence of diarrhea but the incidence of grade 3/4 diarrhea remains high at 28 to 40%.

Study of Glutamine as Prophylaxis for Irinotecan Induced Diarrhea

Cross Cancer Institute

AHS Cancer Control Alberta

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Urinary Bladder Neoplasms

Docetaxel

Tubulin Modulators

Antimitotic Agents

OGX-427 injection at 200mg, 400mg, 600mg, 800mg or 1000mg once a week until withdrawn

OGX-427

injection - 75 mg/M2 IV on Day 1 every 21 days for cohorts 6 \& 7 only, together with appropriate dose of OGX-427 until withdrawn from study

Kim Chi, M.D.

This study is for patients with cancer who have failed potentially curative treatments or for whose disease a curative treatment does not exist.

OGX-427 is an antisense product that inhibits expression of one of the heat shock proteins. Decreasing this heat shock protein (Hsp27) should result in down regulation of pathways implicated in cancer progression and development of resistance to treatment.

This study is for patients with breast, prostate, ovarian, non-small cell lung (NSCL) or bladder cancer who have failed potentially curative treatments or for whose disease a curative treatment does not exist.

OGX-427 is a second-generation ASO that inhibits expression of Hsp27. Hsp27 is one of the heat shock proteins. Hsp27 increases with cell stress, including cytotoxic chemotherapy, radiation therapy and hormone therapy and has been shown to inhibit cell death. Thus, decreasing Hsp27 as a cancer therapy is attractive as a therapy as it should result in down regulation of pathways implicated in cancer progression and development of resistance to treatment.

A number of in vitro and in vivo pharmacological studies have demonstrated that OGX-427 has single-agent activity in reducing Hsp27, inhibiting cell growth and inducing cell death in several human cancer cell lines. OGX-427 has also demonstrated chemosensitizing activity in studies using cell lines and animal models in combination with several cytotoxic drugs, including docetaxel.

Docetaxel (Taxotere®) has anticancer activity in breast, prostate, ovarian, non-small cell lung and bladder cancer. Docetaxel has been approved by Health Canada and the Food and Drug Administration for the treatment of patients with breast, prostate, ovarian and non-small cell lung cancer.

Safety Study of an Antisense Product in Prostate, Ovarian, NSCL, Breast or Bladder Cancer

A Phase 1 Study Evaluating A Second Generation Antisense Oligonucleotide (OGX 427) That Inhibits Heat Shock Protein 27 (Hsp27

Achieve Life Sciences

Trastuzumab

Patients with HER2 positive breast cancer which has become trastuzumab resistent.

Injection with 89Zr-trastuzumab and 89Zr-trastuzumab PET scan.

Imaging with 89Zr-trastuzumab PET

HSP90 inhibition is a potentially new targeted drug modality in the treatment of HER2 positive, trastuzumab refractory breast cancer. Little is known about the pharmacodynamics of HSP90 inhibitors in vivo, but non-invasive PET/CT imaging in a xenograft mouse model could visualize and quantify HER2 reduction after AUY922 treatment by 89Zr-trastuzumab PET imaging. Two doses of 50 mg/kg AUY922 resulted in a decrease in HER2 expression of approximately 50%, quantified 6 days after the last administration of AUY922.

Visualizing HER2 expression in breast cancer patients before and early following HSP90 inhibition by means of 89Zr-trastuzumab PET, is likely to provide insight in the early in vivo effect of HSP90 inhibition and could potentially support patient tailored therapy.

This study is designed as a side study to the multicenter, international phase I-II trial with the HSP90 inhibitor AUY922 (protocol CAUY922A2101), as part of the biomarker assessment. In protocol CAUY922A2101, section 4, the design of this phase I-II trial is described (p36, 37). Briefly, a dose-escalation study is performed according to phase I design. This part is followed by a dose-expansion study according to a phase II design. In the latter part, breast cancer patients are enrolled that are either refractory to hormone- or trastuzumab treatment (both treatment arms, n=40 patients). Patients with HER2 positive, trastuzumab refractory breast cancer, will receive a 89Zr-trastuzumab PET scan as part of the present side study protocol, which will be performed in collaboration with the Royal Marsden Hospital (United Kingdom).

To this end, a 89Zr-trastuzumab PET scan will be performed before (baseline) and during treatment with the HSP90 inhibitor AUY922, as described below.

A minimum of six patients are needed to evaluate whether the 89Zr-trastuzumab PET scan can be used for the detection of a decrease of HER2 expression, induced by HSP90 inhibition.

89Zr-trastuzumab PET for Imaging the Effect of HSP90 Inhibition

Imaging the Effect of HSP90 Inhibitor AUY922 on HER2 Expression by Means of 89Zr-trastuzumab PET. Side Study to Phase I-II Study With AUY922 in Either HER2 or ER Positive Locally Advanced or Metastatic Breast Cancer: Protocol CAUY922A2101

Primary endpoint: measurement of decreased HER2 expression compared to baseline. A decline is defined as a decrease of at least 30% in mean Standardized Uptake Value (SUV) in a maximum of three lesions.

Principal investigator

Nervous System Diseases

Diseases and Abnormalities at or Before Birth

Rare Diseases

Recurrence

Sarcoma

Nerve Sheath Neoplasms

Neurofibrosarcoma

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nervous System Neoplasms

Peripheral Nervous System Neoplasms

Peripheral Nervous System Diseases

Neuromuscular Diseases

Fibrosarcoma

Neoplasms, Fibrous Tissue

Neoplasms, Connective Tissue

Neurofibromatoses

Neurofibroma

Soft Tissue Sarcoma

Malignant Peripheral Nerve Sheath Tumor

Neurofibromatosis

Anti-Infective Agents

Vasoconstrictor Agents

Respiratory System Agents

Sirolimus

Temsirolimus

MTOR Inhibitors

Xylometazoline

Anti-Bacterial Agents

Antibiotics, Antitubercular

Clotrimazole

Miconazole

Antifungal Agents

Immunosuppressive Agents

Immunologic Factors

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

ganetespib

4mg taken orally once daily on a continuous dosing schedule; Loading dose 12 mg on cycle 1 day 1 only.

AeRang Kim, MD, PhD

Brigitte Widemann, MD

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.

SARC023: Ganetespib and Sirolimus in Patients With MPNST (Malignant Peripheral Nerve Sheath Tumors)

A Phase I/II Trial of Ganetespib in Combination With the mTOR Inhibitor Sirolimus for Patients With Recurrent or Refractory Sarcomas Including Unresectable or Metastatic Malignant Peripheral Nerve Sheath Tumors

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.

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.

To describe the plasma pharmacokinetic profile of ganetespib and sirolimus when administered in combination therapy.

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.

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.

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.

To describe the plasma pharmacokinetic profile of ganetespib in terms of half life.

A conventional 3+3 dose escalation design was used for phase 1. All patients in phase 2 were treated with the recommended dose.

Synta Pharmaceuticals Corp.

United States Department of Defense

Sarcoma Alliance for Research through Collaboration

For each 28-day cycle, subjects took doses of both ganetespib + sirolimus:

ganetespib: 150 mg/m² IV on days 1, 8, and 15 intravenously over 1 hour

Sirolimus: 4mg taken orally once daily on a continuous dosing schedule; Loading dose 12 mg on cycle 1 day 1 only.

Phase 1 Dose 1

For each 28-day cycle, subjects took doses of both ganetespib + sirolimus:

ganetespib: 200 mg/m² IV on days 1, 8, and 15 intravenously over 1 hour

Sirolimus: 4mg taken orally once daily on a continuous dosing schedule; Loading dose 12 mg on cycle 1 day 1 only.

Phase 1 Dose 2

Phase 2

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.

Ganetespib / Sirolimus

Phase I

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.

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Sarcoma subtype

Tumor location at diagnosis

Phase 1

History of metastatic disease

Prior chemotherapy regimen

Prior radiation

Prior surgery

SARC

Dose Level 1

Dose Level 2

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.

Number of Dose Limiting Toxicities of Ganetespib When Administered in Combination With Sirolimus.

Clinical Benefit of Ganetespib in Combination With Sirolimus

Dose Level 1- Sirolimus trough

Dose Level 2- Sirolimus trough

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.

Change in Plasma Pharmacokinetic Profile of Ganetespib and Sirolimus When Administered in Combination-Observed Maximum Plasma Concentration (Cmax)

Hsp70 at Baseline

Hsp70 at Cycle 1 Day 15

pAKT at Baseline

pAKT at Cycle 1 Day 15

p-S6 at Baseline

p-S6 at Cycle 1 Day 15

p-eiF2alpha at Baseline

p-eiF2alpha at Cycle 1 Day 15

11 subjects provided consent and had adequate specimens for analysis.

Changes in Pharmacodynamic Parameters in Peripheral Blood Mononuclear Cells

Baseline- Overall pain intensity

Baseline- Tumor pain intensity

Baseline- Pain interference

Prior to Cycle 3- Overall pain intensity

Prior to Cycle 3- Tumor pain intensity

Prior to Cycle 3- Pain interference

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.

Patient-reported Pain Severity and the Impact of Pain on Daily Activities

The 3D-MRI were not measurable with current modalities. Due to their nature and incomplete imaging, volumetric analysis was not feasible.

Utility of Three-dimensional MRI (3D-MRI) Analysis in Comparison to 1-dimensional and 2-dimensional Measurements

Ganetespib half life for dose level 1

Ganetespib half life for dose level 2

10 patients were enrolled in Phase 1 of the study. 1 patient was inevaluable.

Plasma Pharmacokinetic Profile of Ganetespib When Administered in Combination With Sirolimus

Phase 1 Dose Level 1

Phase 1 Dose Level 2

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Imaging HSP90 Inhibitor AUY922 on VEGF-89ZR-bevacizumab Positron Emission Tomography (PET)	NCT01081613	Breast Cancer	89Zr-bevacizuma...	18 Years -	University Medical Center Groningen
Study of Glutamine as Prophylaxis for Irinotecan Induced Diarrhea	NCT00255229	Metastatic Colo...	Glutamine Placebo	18 Years -	AHS Cancer Control Alberta
Safety Study of an Antisense Product in Prostate, Ovarian, NSCL, Breast or Bladder Cancer	NCT00487786	Neoplasms	OGX-427 Docetaxel	18 Years -	Achieve Life Sciences
89Zr-trastuzumab PET for Imaging the Effect of HSP90 Inhibition	NCT01081600	Breast Cancer	Imaging with 89...	18 Years -	University Medical Center Groningen
Study of Glutamine as Prophylaxis for Irinotecan Induced Diarrhea	NCT00255229	Metastatic Colo...	Glutamine Placebo	18 Years -	AHS Cancer Control Alberta
Imaging HSP90 Inhibitor AUY922 on VEGF-89ZR-bevacizumab Positron Emission Tomography (PET)	NCT01081613	Breast Cancer	89Zr-bevacizuma...	18 Years -	University Medical Center Groningen
SARC023: Ganetespib and Sirolimus in Patients With MPNST (Malignant Peripheral Nerve Sheath Tumors)	NCT02008877	Malignant Perip... Sarcoma	ganetespib Sirolimus	16 Years -	Sarcoma Alliance for Research through Collaboration
Safety Study of an Antisense Product in Prostate, Ovarian, NSCL, Breast or Bladder Cancer	NCT00487786	Neoplasms	OGX-427 Docetaxel	18 Years -	Achieve Life Sciences

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