Description:
Part 1 (Phase IA single agent portion) will test the tolerability of continuous twice a day
dosing of GRN-300, a salt-inducible kinase inhibitor, with each cycle consisting of 28 days
of treatment. The number of administered cycles will depend on the tolerability of each dose
level and the severity and occurrence of side effects and DLTs.
Part 2 (Phase IB combination therapy portion) will test the tolerability of continuous 28-day
cycles of GRN-300 in combination with weekly paclitaxel x 3.
Overall duration of the study will be approximately 24 months, depending on the rate of
enrollment and number of subjects enrolled.
Overall duration of the study will be approximately 24 months, depending on the rate of
enrollment and number of subjects enrolled.
Title
- Brief Title: First-in-Human Evaluation of GRN-300 in Subjects With Recurrent Ovarian, Primary Peritoneal, and Fallopian Tube Cancers.
- Official Title: Ph 1/1B Evaluation of the Safety, Pharmacokinetics and Efficacy of GRN-300, a Salt-inducible Kinase Inhibitor, Alone and in Combination With Paclitaxel, in Recurrent Ovarian, Primary Peritoneal, and Fallopian Tube Cancers.
Clinical Trial IDs
- ORG STUDY ID:
GRN300-001
- NCT ID:
NCT04711161
Conditions
Interventions
| Drug | Synonyms | Arms |
|---|
| GRN-300 | SIK Inhibitor | Phase 1a: Single Arm, Open Label (GRN-300 monotherapy) |
| Paclitaxel | Taxane | Phase 1b: Single Arm, Open Label (GRN-300 plus paclitaxel) |
Purpose
Part 1 (Phase IA single agent portion) will test the tolerability of continuous twice a day
dosing of GRN-300, a salt-inducible kinase inhibitor, with each cycle consisting of 28 days
of treatment. The number of administered cycles will depend on the tolerability of each dose
level and the severity and occurrence of side effects and DLTs.
Part 2 (Phase IB combination therapy portion) will test the tolerability of continuous 28-day
cycles of GRN-300 in combination with weekly paclitaxel x 3.
Overall duration of the study will be approximately 24 months, depending on the rate of
enrollment and number of subjects enrolled.
Overall duration of the study will be approximately 24 months, depending on the rate of
enrollment and number of subjects enrolled.
Detailed Description
Part 1: Phase 1A Portion Primary objectives:
- Determination of the recommended Phase II dose (RP2D) of GRN-300 in the study
population.
- To investigate the safety and tolerability of repeated 28-day cycles of oral GRN-300
therapy in subjects with recurrent or metastatic ovarian, fallopian tube, and primary
peritoneal cancer or other advanced solid tumors.
Secondary objectives:
- To evaluate the pharmacokinetic (PK) profile of GRN-300 after oral administration of a
single dose and at steady state.
- To estimate the clinical activity of GRN-300 by determining the clinical benefit rate
(CBR: SD≥6 months/PR/CR) and proportion of patients surviving progression free (PFS) at
six months.
- To obtain pharmacodynamic (PD) data on the effects of single agent GRN-300 on peripheral
blood mononuclear cells (PBMCs, all doses, pHDAC5, pSIK2) and tumor tissue (cohort
expansion phase, SIK2, pSIK2, pp85α, pHDAC5).
- To evaluate biomarkers for polyploidy, PI3K signaling and apoptosis.
Part 2: Phase 1B Portion Primary objectives:
- Determination of the RP2D of GRN-300 in combination with weekly paclitaxel in the study
population.
- To investigate the safety and tolerability of repeated 28-day cycles of daily oral
GRN-300 therapy in combination with weekly paclitaxel x 3 in subjects with recurrent or
metastatic ovarian, fallopian tube, and primary peritoneal cancer or other advanced
solid tumors.
Secondary objectives:
- To evaluate the PK profile of GRN-300 and paclitaxel following administration of a
single dose of each and at steady state.
- To estimate the clinical activity of GRN-300 by determining the clinical benefit rate
(CBR: SD≥6 months/PR/CR) and proportion of patients PFS at 6 months.
- To obtain PD data on the effects of GRN-300 plus paclitaxel on peripheral blood
mononuclear cells (PBMCs, all doses, pHDAC5, pSIK2) and tumor tissue (cohort expansion
phase, SIK2, pSIK2, pp85α, pHDAC5).
- To evaluate biomarkers for polyploidy, PI3K signaling and apoptosis
Exploratory Translational Objectives for Both Portions:
- To determine SIK2 and SIK2 target total protein and phosphorylation levels before and
on-treatment.
- To explore biological difference in tumor biopsies from responders and non- responders.
- To investigate the relationship between plasma concentrations/exposure and changes in
safety and efficacy outputs to facilitate population analysis.
- To determine if GRN-300 impacts bone mass and biochemical markers of bone turnover.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Phase 1a: Single Arm, Open Label (GRN-300 monotherapy) | Experimental | The study will determine the safety of continuous twice a day oral dosing of GRN-300, with each cycle consisting of 28 days of treatment. The number of administered cycles will depend on the tolerability of each dose level and the severity and occurrence of side effects and DLTs. The maximal tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of GRN-300 as a single agent will be determined. The overall duration of Phase 1a will be approximately 9-12 months, depending on the rate of enrollment and the number of subjects enrolled. | |
| Phase 1b: Single Arm, Open Label (GRN-300 plus paclitaxel) | Experimental | The study will determine the safety of continuous twice a day oral dosing of GRN-300, with each cycle consisting of 28 days of treatment, in combination with intravenously administered paclitaxel weekly x 3 during each 28-day cycle. The number of administered cycles will depend on the tolerability of each dose level and the severity and occurrence of side effects and DLTs. The maximal tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of GRN-300 in combination with paclitaxel will be determined. The overall duration of Phase 1b will be approximately 9-12 months, depending on the rate of enrollment and the number of subjects enrolled. Phase 1b will commence following determination of the MTD and RP2D of GRN-300 monotherapy in Phase 1a.
Overall duration of the study will be approximately 24 months, depending on the rate of enrollment and number of subjects enrolled. | |
Eligibility Criteria
Inclusion Criteria:
- Age ≥ 18 years.
- Diagnosis of recurrent ovarian, primary peritoneal or fallopian tube epithelial
cancer, or metastatic solid tumors. Histologic or cytologic confirmation of the
original tumor by MD Anderson Cancer Center Pathology is required.
- Patients must have measurable disease defined as at least one lesion that can be
accurately measured in at least one dimension as defined by RECIST 1.1.
- Prior therapy: Patients must have received at least one prior second-line treatment
for persistent / recurrent disease but may have received any number of prior
treatments.
- ECOG score of 0-1.
- Adequate bone marrow, liver and renal function.
Exclusion Criteria:
- Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug.
- Patients with known hypersensitivity to paclitaxel or residual Grade 2 or higher
neuropathy (excluded from Phase IB portion only).
- Use of any cytotoxic chemotherapy or investigational drugs, biologics, or devices
within 21 days prior to study enrollment.
- Women who are pregnant or breastfeeding.
- Known history of human immunodeficiency virus (HIV) infection or current chronic or
active hepatitis B or C infection requiring treatment with antiviral therapy.
- Known CNS metastases or leptomeningeal disease.
- Gastrointestinal dysfunction that may affect oral drug absorption (e.g., intermittent
or chronic bowel obstruction, short gut, etc.).
- Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular
accident (including transient ischemic attacks) deep vein thrombosis or pulmonary
embolism within six months of start of study treatment.
- Other medical co-morbidities that in the investigator's judgment would increase the
risks of participation
- QTc >480 msec be excluded from the study
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Phase 1A Portion - Determination of GRN-300 monotherapy RP2D in the study population. |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • Determination of the recommended Phase II dose (RP2D) of GRN-300 in the study population. |
Secondary Outcome Measures
| Measure: | Phase 1A - Determination of GRN-300 monotherapy PK profile (Cmax). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • To evaluate the pharmacokinetic (PK) profile of GRN-300 after oral administration of a single dose and at steady state.
- Maximum plasma concentration (Cmax) |
| Measure: | Phase 1A - Determination of GRN-300 monotherapy PK profile (tmax). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • To evaluate the pharmacokinetic (PK) profile of GRN-300 after oral administration of a single dose and at steady state.
- Time to Cmax (tmax) |
| Measure: | Phase 1A - Determination of GRN-300 monotherapy PK profile (t1/2). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • To evaluate the pharmacokinetic (PK) profile of GRN-300 after oral administration of a single dose and at steady state.
- Terminal half-life (t1/2) |
| Measure: | Phase 1A - Determination of GRN-300 monotherapy PK profile (AUC0-t). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • To evaluate the pharmacokinetic (PK) profile of GRN-300 after oral administration of a single dose and at steady state.
- Area under the plasma concentration-time curve from zero to the last measurable concentration (AUC0-t) |
| Measure: | Phase 1A - Determination of GRN-300 monotherapy PK profile (AUC0-Inf). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • To evaluate the pharmacokinetic (PK) profile of GRN-300 after oral administration of a single dose and at steady state.
- Area under the plasma concentration-time curve from zero to infinity (AUC0-Inf) |
| Measure: | Phase 1A - Determination of GRN-300 monotherapy PK profile (CL/F). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • To evaluate the pharmacokinetic (PK) profile of GRN-300 after oral administration of a single dose and at steady state.
- Apparent oral clearance (CL/F) |
| Measure: | Phase 1A - Determination of GRN-300 monotherapy PK profile (Vz/F). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • To evaluate the pharmacokinetic (PK) profile of GRN-300 after oral administration of a single dose and at steady state.
- Apparent volume of distribution during terminal distribution phase (Vz/F) |
| Measure: | Phase 1A - Estimation of the clinical activity of GRN-300 (CBR). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • Determination of the clinical benefit rate (CBR: SD≥6 months/PR/CR) |
| Measure: | Phase 1A - Estimation of the clinical activity of GRN-300 (PFS). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • Proportion of patients surviving progression-free (PFS) at 6 months |
| Measure: | Phase 1A - Pharmacodynamic (PD) data on the effects of GRN-300 on peripheral blood mononuclear cells (PBMCs) (pHDAC5). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • Determination of pHDAC5 |
| Measure: | Phase 1A - Pharmacodynamic (PD) data on the effects of GRN-300 on peripheral blood mononuclear cells (PBMCs) (pSIK2). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • Determination of pSIK2 |
| Measure: | Phase 1A - Pharmacodynamic (PD) data on the effects of GRN-300 on tumor tissue (SIK2). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • Determination of SIK2 |
| Measure: | Phase 1A - Pharmacodynamic (PD) data on the effects of GRN-300 on tumor tissue (pSIK2). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • Determination of pSIK2 |
| Measure: | Phase 1A - Pharmacodynamic (PD) data on the effects of GRN-300 on tumor tissue (pp85alpha). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • Determination of pp85alpha |
| Measure: | Phase 1A - Pharmacodynamic (PD) data on the effects of GRN-300 on tumor tissue (pHDAC5). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • Determination of pHDAC5 |
| Measure: | Phase 1A - Evaluation of biomarkers (polyploidy). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • Determination of biomarkers for polyploidy |
| Measure: | Phase 1A - Evaluation of biomarkers (PI3K). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • Determination of biomarkers for PI3K signaling |
| Measure: | Phase 1A - Evaluation of biomarkers (apoptosis). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • Determination of biomarkers for apoptosis |
| Measure: | Phase 1B - Determination of GRN-300 with paclitaxel PK profile (Cmax). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • To evaluate the PK profile of GRN-300 and paclitaxel following administration of a single dose of each and at steady state.
- Maximum plasma concentration (Cmax) |
| Measure: | Phase 1B - Determination of GRN-300 with paclitaxel PK profile (tmax). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • To evaluate the PK profile of GRN-300 and paclitaxel following administration of a single dose of each and at steady state.
- Time to Cmax (tmax) |
| Measure: | Phase 1B - Determination of GRN-300 with paclitaxel PK profile (t1/2). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • To evaluate the PK profile of GRN-300 and paclitaxel following administration of a single dose of each and at steady state.
- Terminal half-life (t1/2) |
| Measure: | Phase 1B - Determination of GRN-300 with paclitaxel PK profile (AUC0-t). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • To evaluate the PK profile of GRN-300 and paclitaxel following administration of a single dose of each and at steady state.
- Area under the plasma concentration-time curve from zero to the last measurable concentration (AUC0-t) |
| Measure: | Phase 1B - Determination of GRN-300 with paclitaxel PK profile (AUC0-Inf). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • To evaluate the PK profile of GRN-300 and paclitaxel following administration of a single dose of each and at steady state.
- Area under the plasma concentration time curve from zero to infinity (AUC0-Inf) |
| Measure: | Phase 1B - Determination of GRN-300 with paclitaxel PK profile (CL/F). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • To evaluate the PK profile of GRN-300 and paclitaxel following administration of a single dose of each and at steady state.
- Apparent oral clearance (CL/F) |
| Measure: | Phase 1B - Determination of GRN-300 with paclitaxel PK profile (Vz/F). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • To evaluate the PK profile of GRN-300 and paclitaxel following administration of a single dose of each and at steady state.
- Apparent volume of distribution during terminal distribution phase (Vz/F) |
| Measure: | Phase 1B - Estimation of the clinical activity of GRN-300 with paclitaxel (CBR). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • Determination of the clinical benefit rate (CBR: SD≥6 months/PR/CR) |
| Measure: | Phase 1B - Estimation of the clinical activity of GRN-300 with paclitaxel (PFS). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • Proportion of patients surviving progression free (PFS) at 6 months |
| Measure: | Phase 1B - Pharmacodynamic (PD) data on the effects of GRN-300 with paclitaxel on peripheral blood mononuclear cells (PBMCs) (pHDAC5). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • Determination of pHDAC5 |
| Measure: | Phase 1B - Pharmacodynamic (PD) data on the effects of GRN-300 with paclitaxel on peripheral blood mononuclear cells (PBMCs) (pSIK2). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • Determination of pSIK2 |
| Measure: | Phase 1B - Pharmacodynamic (PD) data on the effects of GRN-300 with paclitaxel on tumor tissue (SIK2). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • Determination of SIK2 |
| Measure: | Phase 1B - Pharmacodynamic (PD) data on the effects of GRN-300 with paclitaxel on tumor tissue (pSIK2). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • Determination of pSIK2 |
| Measure: | Phase 1B - Pharmacodynamic (PD) data on the effects of GRN-300 with paclitaxel on tumor tissue (pp85alpha). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • Determination of pp85alpha |
| Measure: | Phase 1B - Pharmacodynamic (PD) data on the effects of GRN-300 with paclitaxel on tumor tissue (pHDAC5). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • Determination of pHDAC5 |
| Measure: | Phase 1B - Evaluation of biomarkers (polyploidy). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • Determination of biomarkers for polyploidy |
| Measure: | Phase 1B - Evaluation of biomarkers (PI3K signaling). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • Determination of biomarkers for PI3K signaling |
| Measure: | Phase 1B - Evaluation of biomarkers (apoptosis). |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | • Determination of biomarkers for apoptosis |
Details
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Green3Bio, Inc. |
Last Updated
January 15, 2021
