Neoplasms

Blood and Lymph Conditions

All Conditions

Heart and Blood Diseases

Rare Diseases

Polycythemia Vera

Polycythemia

Thrombocytosis

Thrombocythemia, Essential

Hematologic Diseases

Bone Marrow Neoplasms

Hematologic Neoplasms

Bone Marrow Diseases

Myeloproliferative Disorders

Blood Platelet Disorders

Hemostatic Disorders

Blood Coagulation Disorders

Hemorrhagic Disorders

Essential Thrombocythemia

Chronic Myeloproliferative Disorders

All Drugs and Chemicals

Imetelstat

Motesanib diphosphate

Enzyme Inhibitors

Protein Kinase Inhibitors

Induction dosing of 9.4 mg/kg weekly, followed by intermittent maintenance dosing.

This is a phase II open-label study of single agent imetelstat in patients with essential thrombocytopenia or with polycythemia vera who have failed or are intolerant to at least one prior therapy, or who refuse standard therapy.

For patients with ET: To obtain a preliminary estimate of efficacy of imetelstat, as measured by best hematologic response within the first year of therapy in patients with ET who have failed or are intolerant to at least one prior therapy, or who have refused standard therapy.

For patients with PV: To obtain a preliminary estimate of efficacy of imetelstat, as measured by maintenance of Hct \< 45% in men and \< 42% in women (or pre-specified Hct count that is tolerable) without phlebotomy or myelosuppressive therapy within the first year of therapy in patients with PV who have failed or are intolerant to at least one prior therapy, or who have refused standard therapy.

Open Label Study to Evaluate the Activity of Imetelstat in Patients With Essential Thrombocythemia or Polycythemia Vera

A Phase II Trial to Evaluate the Activity of Imetelstat (GRN163L) in Patients With Essential Thrombocythemia or Polycythemia Vera Who Require Cytoreduction and Have Failed or Are Intolerant to Previous Therapy, or Who Refuse Standard Therapy

Primary objectives are as follows: ET patients - best hematologic response within the first year of therapy and PV patients - maintenance of Hct \< 45% in men and \< 42% in women (or pre-specified Hct count that is tolerable) without phlebotomy or myelosuppressive therapy within the first year of therapy. Secondary objectives, to determine the durability of hematologic response and to determine the rate of phlebotomy required within the first year of therapy.

The safety and tolerability of imtelstat will be assessed by the incidence, nature, relatedness and severity of adverse events, laboratory abnormalities and vital signs.

Geron Corporation

Skin and Connective Tissue Diseases

Symptoms and General Pathology

Breast Neoplasms

Recurrence

Breast Diseases

Skin Diseases

Disease Attributes

Antineoplastic Agents

Paclitaxel

Bevacizumab

Albumin-Bound Paclitaxel

Tubulin Modulators

Antimitotic Agents

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Imetelstat is administered at a dose of 300 mg/m2 on day one of a 21 day cycle.

Imetelstat sodium

Bevacizumab is administered at 15 mg/kg on day one of a 21 day cycle

Paclitaxel is administered at 90 mg/m2 on days one and eight of a 21 day cycle

Ted Shih, PharmD

Kathy Miller, MD

The purpose of this study is to evaluate the efficacy and safety of treatment with imetelstat + paclitaxel (with or without bevacizumab) versus paclitaxel (with or without bevacizumab) alone for patients with locally recurrent or metastatic breast cancer who have not received chemotherapy or have received one non-taxane based chemotherapy for metastatic breast cancer.

Patients will be randomized in a 1:1 ratio to imetelstat + paclitaxel (with or without bevacizumab) versus paclitaxel (with or without bevacizumab) alone.

Imetelstat in Combination With Paclitaxel (With or Without Bevacizumab) in Patients With Locally Recurrent or Metastatic Breast Cancer

A Randomized Phase II Study Of Imetelstat (GRN163L) In Combination With Paclitaxel (With Or Without Bevacizumab) in Patients With Locally Recurrent Or Metastatic Breast Cancer

Defined as the time from randomization to documented disease progression, as determined by the investigator's assessment according to RECIST, or death from any cause, whichever occurs first.

Objective response as determined by the investigator according to RECIST for patients with measurable disease at baseline.

Clinical response rate includes patients with objective response and stable disease lasting at least 6 months.

Respiratory Tract (Lung and Bronchial) Diseases

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

imetelstat plus standard of care (bevacizumab or observation)

9.4 mg/kg over a 2 hour IV infusion on Day 1 and Day 8 of each 21 day cycle until disease progression.

imetelstat

Dosage and duration will be according to the FDA-approved bevacizumab package insert. Bevacizumab will be administered on Day 1 of each 21-day cycle.

Joan Schiller, MD

The purpose of this is to evaluate the efficacy and safety of imetelstat (GRN163L) as maintenance therapy for patients with advanced stage NSCLC who have not progressed after 4 cycles of platinum based therapy.

Participants will be randomized in a 2:1 ratio to imetelstat + standard of care versus standard of care alone. Participants who received bevacizumab with their induction chemotherapy will continue to receive bevacizumab on this study.

Imetelstat as Maintenance Therapy After Initial Induction Chemotherapy in Non-small Cell Lung Cancer (NSCLC)

A Randomized Phase II Study of Imetelstat as Maintenance Therapy After Initial Induction Chemotherapy for Advance Non-small Cell Lung Cancer(NSCLC)

Defined as the time from randomization to documented disease progression or death, whichever occurs earlier,as determined by the Investigator's assessment according to RECIST, or death from any cause, whichever occurs earlier.

Objective response (partial response plus complete response) occurring post-randomization as determined by the Investigator's assessment according to RECIST criteria using post-induction tumor dimensions as a baseline.

Defined as the time from the date of radomization to death from any cause during the study period.

Safety and tolerability will be assessed by the incidence, nature, and severity of adverse events, laboratory abnormalities, and vital signs.

Nervous System Diseases

Glioblastoma

Glioma

Brain Neoplasms

Diffuse Intrinsic Pontine Glioma

Astrocytoma

Ependymoma

Oligodendroglioma

Brain Stem Neoplasms

Gliosarcoma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Infratentorial Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Anaplastic Astrocytoma

Anaplastic Ependymoma

Neuroepithelioma

Molecular Biology Phase: Patients will receive one infusion of imetelstat prior to surgery. Surgery will take place 12-24 hours after the infusion of imetelstat. Patients will continue to receive therapy on the same schedule as the Phase II patients starting 14-21 days after surgery.

Phase II: Patients receive imetelstat sodium IV over 2 hours on days 1 and 8. Treatment repeats every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

imetelstat sodium

Maryam Fouladi

This molecular biology and phase II trial studies how well imetelstat sodium works in treating younger patients with recurrent or refractory brain tumors. Imetelstat sodium may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

\* Molecular Biology:

I. To test the ability of imetelstat (GRN163L) to inhibit telomerase activity by Telomere Repeat Amplification Protocol (TRAP) in tumor and peripheral blood mononuclear cells (PBMNCs) of children with recurrent or refractory HGG or ependymoma.

II. To characterize the pharmacokinetics of imetelstat in plasma, cerebrospinal fluid (CSF), and tumor tissue of children with recurrent or refractory HGG or ependymoma.

\* Phase II:

I. To estimate the sustained objective response rates (complete response (CR) plus partial response (PR), sustained for at least 6 weeks) to imetelstat administered intravenously on Days 1 and 8 of a 21-day course at the recommended Phase II pediatric dose, 285mg/m2, in children with recurrent or refractory HGG, ependymoma or DIPG. Independent estimates of the objective response rates will be made for each of the three strata, two of which are histologically defined.

SECONDARY OBJECTIVES:

\* Phase II only:

I. To assess evidence of telomerase expression by detection of hTERT mRNA and TERC RNA levels by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and telomerase activity by TRAP in archival tumor tissue (for HGG, and ependymoma strata) and to explore association of telomerase positivity with objective response and progression-free survival (PFS).

II. To estimate the stratum-specific PFS distributions of children with recurrent or refractory HGG, ependymoma or DIPG treated with imetelstat.

\* Molecular Biology and Phase II:

I. To characterize the plasma and CSF pharmacokinetics of imetelstat in children with recurrent or refractory HGG, ependymoma or DIPG.

II. To assess evidence of telomerase expression by detection of hTERT mRNA and TERC RNA levels by qRT-PCR, telomerase activity by TRAP, and telomere length by telomere terminal restriction fragment (TRF) analysis in PBMNCs prior to treatment with imetelstat and to assess evidence of telomerase inhibition by TRAP and telomere shortening by TRF analysis serially on treatment with imetelstat.

III. To compare incidence of Alternative Lengthening of Telomeres (ALT) mechanism in pediatric HGG, or ependymoma as determined by four different assays 1) ATRX/DAXX nuclear localization by immunofluorescence (IF) assay; 2) telomere-specific signal by fluorescence in situ hybridization (FISH); 3) telomeric terminal restriction fragment (TRF) analysis by Southern blot; and 4) by C circle assay and to assess correlation of these methods for ALT detection.

IV. To assess whether ALT status is associated with objective response rates for children with recurrent or refractory HGG, or ependymoma treated with imetelstat.

V. To describe MRI characteristics and diffusion changes of recurrent or refractory HGG, ependymoma and DIPG tumors prior to and after treatment with imetelstat to assess for an early diffusion indicator of response.

VI. To measure telomere length of tumors in children with recurrent or refractory HGG, or ependymoma and to assess association of tumor length with tumor response to imetelstat treatment.

VII. To assess hTERT promoter mutations and methylation, H3F3A, ATRX, and DAXX mutations, and examine the effects of these modifications in children with recurrent brain tumors using targeted gene, exome, RNA sequencing and methylation arrays of targeted genomic regions.

OUTLINE:

Molecular Biology Phase: Patients will receive one infusion of imetelstat prior to surgery. Surgery will take place 12-24 hours after the infusion of imetelstat. Patients will continue to receive therapy on the same schedule as the Phase II patients starting 14-21 days after surgery.

Phase II: Patients receive imetelstat sodium IV over 2 hours on days 1 and 8. Treatment repeats every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Imetelstat Sodium in Treating Younger Patients With Recurrent or Refractory Brain Tumors

A Molecular Biology and Phase II Study of Imetelstat (GRN163L) in Children With Recurrent High-Grade Glioma, Ependymoma and Diffuse Intrinsic Pontine Glioma

Other PBTC investigators can develop a concept proposal and submit it to the PBTC Scientific Committee for a decision to share data and to what extent to share it.

This outcome measure is for the Molecular biology study only. The assessment was done to identify cases with at least 50% reduction in telomerase activity.

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=50% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR sustained for at least 6 weeks.

For each stratum separately exact confidence interval estimates will be provided for the true, unknown rates of objective response. Estimated by cumulative incidence functions.

This outcome measure is applicable only for the Molecular biology study arm. Telomerase inhibition was assessed in PBMCs and summarised as 'yes-inhibited' vs. 'no inhibition'

Kaplan-Meier estimates of distributions of survival and PFS for all eligible subjects who received at least one dose of imetelstat will be provided separately.

This secondary objective is for Stratum-B and C only, which enroll HGG and ependymoma patients. We will describe the evidence of telomerase expression by detection of hTERT mRNA and TERC RNA levels by qRT-PCR and telomerase activity by TRAP in archival tumor tissue; Association of telomerase positivity with objective response and PFS will not be able to be conducted as the study was terminated early and there was no objective response.

This outcome measure was for both Molecular biology and Phase II studies. We will not be able to present the results of this objective as the study was terminated early.

National Cancer Institute (NCI)

Pediatric Brain Tumor Consortium

The AEs we report were experienced while the participants were on study.

Molecular Study arm for Recurrent or Refractory Medulloblastoma/PNET Patients

Molecular Study-A

Molecular Study arm for Recurrent or refractory high-grade glioma patients

Molecular Study-B

This is the Phase-II stratum for Recurrent or Refractory Medulloblastoma/PNET Patients

Stratum-A

This is the Phase-II stratum for Recurrent or refractory high-grade glioma patients

Stratum-B

This is the Phase-II stratum for Recurrent or refractory ependymoma patients

Stratum-C

This is the Phase-II stratum for Recurrent or refractory diffuse intrinsic pontine gliomas (DIPG) patients

Stratum-D

This is the Molecular Biology arm for Medulloblastoma/PNET Patients

Molecular Biology Stratum-A

This is the Molecular Biology arm for High-Grade Glioma Patients

Molecular Biology Stratum-B

Total

Age, Continuous

Sex: Female, Male

Dr. Mehmet Kocak

Molecular Biology Phase: Patients will receive one infusion of imetelstat prior to surgery. Surgery will take place 12-24 hours after the infusion of imetelstat. Patients will continue to receive therapy on the same schedule as the Phase II patients starting 14-21 days after surgery.

Phase II: Patients receive imetelstat sodium IV over 2 hours on days 1 and 8. Treatment repeats every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

imetelstat sodium: Given IV

Molecular Biology Study

This outcome measure is only for the molecular biology study. Telomerase inhibition was assessed and the inhibition level was compared with the baseline level to identify increased inhibition.

Numver of Patients With Telomerase-positive Archival Tumors Who Demonstrate at Least 50% Reduction

This is the Phase-II stratum for Recurrent or refractory diffuse intrinsic pontine glioma patients

This is the Phase-II study cohort, excluding the molecular study patients.

Phase II: Stratum-specific Objective Response (CR+PR) Rate

Samples from six patients were consequently considered evaluable and were analyzed.

Number of Participants With Telomerase Inhibition

Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

Stratum-specific Progression-free Survival (PFS) (Phase II)

TRAP

TERT

TERC

This objective is for HGG and ependymoma patients only.

This objective is for STRATUM-C patients only, having only 4 patients with TRAP, TERT and TERC levels measured. Due to small sample and having no objective response, association studies of these markers with Objective Reponse and PFS were not possible. Therefore, we only report the the percentage of cases with at least weak TRAP activity.

Number of Patients With Telomerase Expression Data by Detection of hTERT mRNA and TERC RNA Levels by qRT-PCR and Telomerase Activity by TRAP in Archival Tumor Tissue and to Explore Association of Telomerase Positivity With Objective Response and PFS

Treatment (Imetelstat Sodium)

This study has been terminated early and the study team decided not to pursue this aim as the results would be inconclusive due to small sample size. Neither the neuroimaging, nor the biology data are available for these patients.

Quantitative MRI Parameters of Tumors Prior to and After Treatment With Imetelstat (Molecular Biology and Phase II Studies)

This is the Molecular Biology arm for Ependymoma Patients

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Open Label Study to Evaluate the Activity of Imetelstat in Patients With Essential Thrombocythemia or Polycythemia Vera	NCT01243073	Essential Throm... Polycythemia Ve...	Imetelstat	18 Years -	Geron Corporation
Imetelstat in Combination With Paclitaxel (With or Without Bevacizumab) in Patients With Locally Recurrent or Metastatic Breast Cancer	NCT01256762	Locally Recurre...	Imetelstat sodi... Bevacizumab Paclitaxel	18 Years -	Geron Corporation
Imetelstat in Combination With Paclitaxel (With or Without Bevacizumab) in Patients With Locally Recurrent or Metastatic Breast Cancer	NCT01256762	Locally Recurre...	Imetelstat sodi... Bevacizumab Paclitaxel	18 Years -	Geron Corporation
Imetelstat as Maintenance Therapy After Initial Induction Chemotherapy in Non-small Cell Lung Cancer (NSCLC)	NCT01137968	Non-small Cell ...	imetelstat Bevacizumab	18 Years -	Geron Corporation
Imetelstat Sodium in Treating Younger Patients With Recurrent or Refractory Brain Tumors	NCT01836549	Anaplastic Astr... Anaplastic Epen... Astrocytoma, Gr... Ependymoma Giant Cell Glio... Glioblastoma Gliosarcoma Oligodendroglio... Brainstem Tumor...	imetelstat sodi...	12 Months - 21 Years	Pediatric Brain Tumor Consortium
Imetelstat Sodium in Treating Younger Patients With Recurrent or Refractory Brain Tumors	NCT01836549	Anaplastic Astr... Anaplastic Epen... Astrocytoma, Gr... Ependymoma Giant Cell Glio... Glioblastoma Gliosarcoma Oligodendroglio... Brainstem Tumor...	imetelstat sodi...	12 Months - 21 Years	Pediatric Brain Tumor Consortium

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