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First-in-Human Evaluation of GRN-300 in Subjects With Recurrent Ovarian, Primary Peritoneal, and Fallopian Tube Cancers.

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ClinicalTrials.gov Identifier: NCT04711161
Recruitment Status : Recruiting
First Posted : January 15, 2021
Last Update Posted : January 15, 2021
Sponsor:
Information provided by (Responsible Party):
Green3Bio, Inc.

Study Description
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Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Ovarian Tumors Drug: GRN-300 Drug: Paclitaxel Phase 1

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.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 64 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Intervention Model Description: GRN-300 alone and in combination with paclitaxel.
Masking: None (Open Label)
Primary Purpose: Treatment
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.
Actual Study Start Date : December 21, 2020
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : March 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Paclitaxel

Arms and Interventions
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Arm Intervention/treatment
Experimental: Phase 1a: Single Arm, Open Label (GRN-300 monotherapy)
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.
 Drug: GRN-300
A salt-inducible kinase inhibitor
Other Name: SIK Inhibitor
Experimental: Phase 1b: Single Arm, Open Label (GRN-300 plus paclitaxel)

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.

 Drug: GRN-300
A salt-inducible kinase inhibitor
Other Name: SIK Inhibitor

Drug: Paclitaxel
Microtubule inhibitor
Other Name: Taxane


Outcome Measures
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Primary Outcome Measures :
  1. Phase 1A Portion - Determination of GRN-300 monotherapy RP2D in the study population. [ Time Frame: 24 months ]
    • Determination of the recommended Phase II dose (RP2D) of GRN-300 in the study population.

  2. Phase 1A Portion - Number of participants with treatment-related adverse events as assessed by CTCAE v5.0. [ Time Frame: 24 months ]
    • To investigate the safety 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, based on the number of participants with treatment-related adverse events as assessed by CTCAE v5.0.

  3. Phase 1B Portion - Determination of GRN-300 with paclitaxel RP2D in the study population. [ Time Frame: 24 months ]
    • Determination of the recommended Phase II dose (RP2D) of GRN-300 in combination with weekly paclitaxel in the study population.

  4. Phase 1B Portion - Number of participants with treatment-related adverse events as assessed by CTCAE v5.0. [ Time Frame: 24 months ]
    • To investigate the safety 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, based on the number of participants with treatment-related adverse events as assessed by CTCAE v5.0.


Secondary Outcome Measures :
  1. Phase 1A - Determination of GRN-300 monotherapy PK profile (Cmax). [ Time Frame: 24 months ]

    • To evaluate the pharmacokinetic (PK) profile of GRN-300 after oral administration of a single dose and at steady state.

    - Maximum plasma concentration (Cmax)


  2. Phase 1A - Determination of GRN-300 monotherapy PK profile (tmax). [ Time Frame: 24 months ]

    • To evaluate the pharmacokinetic (PK) profile of GRN-300 after oral administration of a single dose and at steady state.

    - Time to Cmax (tmax)


  3. Phase 1A - Determination of GRN-300 monotherapy PK profile (t1/2). [ Time Frame: 24 months ]

    • 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)


  4. Phase 1A - Determination of GRN-300 monotherapy PK profile (AUC0-t). [ Time Frame: 24 months ]

    • 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)


  5. Phase 1A - Determination of GRN-300 monotherapy PK profile (AUC0-Inf). [ Time Frame: 24 months ]

    • 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)


  6. Phase 1A - Determination of GRN-300 monotherapy PK profile (CL/F). [ Time Frame: 24 months ]

    • 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)


  7. Phase 1A - Determination of GRN-300 monotherapy PK profile (Vz/F). [ Time Frame: 24 months ]

    • 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)


  8. Phase 1A - Estimation of the clinical activity of GRN-300 (CBR). [ Time Frame: 24 months ]
    • Determination of the clinical benefit rate (CBR: SD≥6 months/PR/CR)

  9. Phase 1A - Estimation of the clinical activity of GRN-300 (PFS). [ Time Frame: 24 months ]
    • Proportion of patients surviving progression-free (PFS) at 6 months

  10. Phase 1A - Pharmacodynamic (PD) data on the effects of GRN-300 on peripheral blood mononuclear cells (PBMCs) (pHDAC5). [ Time Frame: 24 months ]
    • Determination of pHDAC5

  11. Phase 1A - Pharmacodynamic (PD) data on the effects of GRN-300 on peripheral blood mononuclear cells (PBMCs) (pSIK2). [ Time Frame: 24 months ]
    • Determination of pSIK2

  12. Phase 1A - Pharmacodynamic (PD) data on the effects of GRN-300 on tumor tissue (SIK2). [ Time Frame: 24 months ]
    • Determination of SIK2

  13. Phase 1A - Pharmacodynamic (PD) data on the effects of GRN-300 on tumor tissue (pSIK2). [ Time Frame: 24 months ]
    • Determination of pSIK2

  14. Phase 1A - Pharmacodynamic (PD) data on the effects of GRN-300 on tumor tissue (pp85alpha). [ Time Frame: 24 months ]
    • Determination of pp85alpha

  15. Phase 1A - Pharmacodynamic (PD) data on the effects of GRN-300 on tumor tissue (pHDAC5). [ Time Frame: 24 months ]
    • Determination of pHDAC5

  16. Phase 1A - Evaluation of biomarkers (polyploidy). [ Time Frame: 24 months ]
    • Determination of biomarkers for polyploidy

  17. Phase 1A - Evaluation of biomarkers (PI3K). [ Time Frame: 24 months ]
    • Determination of biomarkers for PI3K signaling

  18. Phase 1A - Evaluation of biomarkers (apoptosis). [ Time Frame: 24 months ]
    • Determination of biomarkers for apoptosis

  19. Phase 1B - Determination of GRN-300 with paclitaxel PK profile (Cmax). [ Time Frame: 24 months ]

    • 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)


  20. Phase 1B - Determination of GRN-300 with paclitaxel PK profile (tmax). [ Time Frame: 24 months ]

    • 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)


  21. Phase 1B - Determination of GRN-300 with paclitaxel PK profile (t1/2). [ Time Frame: 24 months ]

    • 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)


  22. Phase 1B - Determination of GRN-300 with paclitaxel PK profile (AUC0-t). [ Time Frame: 24 months ]

    • 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)


  23. Phase 1B - Determination of GRN-300 with paclitaxel PK profile (AUC0-Inf). [ Time Frame: 24 months ]

    • 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)


  24. Phase 1B - Determination of GRN-300 with paclitaxel PK profile (CL/F). [ Time Frame: 24 months ]

    • 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)


  25. Phase 1B - Determination of GRN-300 with paclitaxel PK profile (Vz/F). [ Time Frame: 24 months ]

    • 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)


  26. Phase 1B - Estimation of the clinical activity of GRN-300 with paclitaxel (CBR). [ Time Frame: 24 months ]
    • Determination of the clinical benefit rate (CBR: SD≥6 months/PR/CR)

  27. Phase 1B - Estimation of the clinical activity of GRN-300 with paclitaxel (PFS). [ Time Frame: 24 months ]
    • Proportion of patients surviving progression free (PFS) at 6 months

  28. Phase 1B - Pharmacodynamic (PD) data on the effects of GRN-300 with paclitaxel on peripheral blood mononuclear cells (PBMCs) (pHDAC5). [ Time Frame: 24 months ]
    • Determination of pHDAC5

  29. Phase 1B - Pharmacodynamic (PD) data on the effects of GRN-300 with paclitaxel on peripheral blood mononuclear cells (PBMCs) (pSIK2). [ Time Frame: 24 months ]
    • Determination of pSIK2

  30. Phase 1B - Pharmacodynamic (PD) data on the effects of GRN-300 with paclitaxel on tumor tissue (SIK2). [ Time Frame: 24 months ]
    • Determination of SIK2

  31. Phase 1B - Pharmacodynamic (PD) data on the effects of GRN-300 with paclitaxel on tumor tissue (pSIK2). [ Time Frame: 24 months ]
    • Determination of pSIK2

  32. Phase 1B - Pharmacodynamic (PD) data on the effects of GRN-300 with paclitaxel on tumor tissue (pp85alpha). [ Time Frame: 24 months ]
    • Determination of pp85alpha

  33. Phase 1B - Pharmacodynamic (PD) data on the effects of GRN-300 with paclitaxel on tumor tissue (pHDAC5). [ Time Frame: 24 months ]
    • Determination of pHDAC5

  34. Phase 1B - Evaluation of biomarkers (polyploidy). [ Time Frame: 24 months ]
    • Determination of biomarkers for polyploidy

  35. Phase 1B - Evaluation of biomarkers (PI3K signaling). [ Time Frame: 24 months ]
    • Determination of biomarkers for PI3K signaling

  36. Phase 1B - Evaluation of biomarkers (apoptosis). [ Time Frame: 24 months ]
    • Determination of biomarkers for apoptosis


Other Outcome Measures:
  1. Exploratory Outcomes (Pharmacologic effects of GRN-300) (SIK2 total protein and phosphorylation) [ Time Frame: 24 months ]
    • To determine SIK2 and SIK2 target total protein and phosphorylation levels before and on-treatment.

  2. Exploratory Outcomes (Pharmacologic effects of GRN-300) (Biological differences in tumor biopsies from responders and non-responders) (SIK2) [ Time Frame: 24 months ]
    • To explore biological differences in tumor biopsies from responders and non-responders (IHC for SIK2).

  3. Exploratory Outcomes (Pharmacologic effects of GRN-300) (Biological differences in tumor biopsies from responders and non-responders) (pSIK2) [ Time Frame: 24 months ]
    • To explore biological differences in tumor biopsies from responders and non-responders (IHC for pSIK2).

  4. Exploratory Outcomes (Pharmacologic effects of GRN-300) (Biological differences in tumor biopsies from responders and non-responders) (p85alpha) [ Time Frame: 24 months ]
    • To explore biological differences in tumor biopsies from responders and non-responders (IHC for p85alpha).

  5. Exploratory Outcomes (Pharmacologic effects of GRN-300) (Biological differences in tumor biopsies from responders and non-responders) (HDAC5) [ Time Frame: 24 months ]
    • To explore biological differences in tumor biopsies from responders and non-responders (IHC for HDAC5).

  6. Exploratory Outcomes (Pharmacologic effects of GRN-300) (Biological differences in tumor biopsies from responders and non-responders) (pHDAC5) [ Time Frame: 24 months ]
    • To explore biological differences in tumor biopsies from responders and non-responders (IHC for pHDAC5).

  7. Exploratory Outcomes (Pharmacologic effects of GRN-300) (Biological differences in tumor biopsies from responders and non-responders) (pAKT) [ Time Frame: 24 months ]
    • To explore biological differences in tumor biopsies from responders and non-responders (IHC for pAKT).

  8. Exploratory Outcomes (Pharmacologic effects of GRN-300) (Biological differences in tumor biopsies from responders and non-responders) (Survivin) [ Time Frame: 24 months ]
    • To explore biological differences in tumor biopsies from responders and non-responders (IHC for survivin).

  9. Exploratory Outcomes (Pharmacologic effects of GRN-300) (Biological differences in tumor biopsies from responders and non-responders) (Cleaved caspase 3) [ Time Frame: 24 months ]
    • To explore biological differences in tumor biopsies from responders and non-responders (IHC for cleaved caspase 3).

  10. Exploratory Outcomes (Pharmacologic effects of GRN-300) (Biological differences in tumor biopsies from responders and non-responders) (Cleaved PARP) [ Time Frame: 24 months ]
    • To explore biological differences in tumor biopsies from responders and non-responders (IHC for cleaved PARP).

  11. Exploratory Outcomes (Pharmacologic effects of GRN-300) (Bone mass) [ Time Frame: 24 months ]
    • To determine if GRN-300 impacts bone mass (Bone Density [DXA] Scan).

  12. Exploratory Outcomes (Pharmacologic effects of GRN-300) (Bone turnover) (Procollagen I Intact N-terminus [P1NP]) [ Time Frame: 24 months ]
    • To determine if GRN-300 impacts biochemical markers of bone turnover (Procollagen I Intact N-terminus [P1NP]).

  13. Exploratory Outcomes (Pharmacologic effects of GRN-300) (Bone turnover) (Osteocalcin) [ Time Frame: 24 months ]
    • To determine if GRN-300 impacts biochemical markers of bone turnover (osteocalcin).

  14. Exploratory Outcomes (Pharmacologic effects of GRN-300) (Bone turnover) (C-terminal telopeptide [CTX]) [ Time Frame: 24 months ]
    • To determine if GRN-300 impacts biochemical markers of bone turnover (C-terminal telopeptide [CTX]).


Eligibility Criteria
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Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04711161


Contacts
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Contact: Steve Morris, MD (901) 277-5582 steve.morris@greenfirebio.com
Contact: Patti Hunker 317.750.0237 phunker@pearlpathways.com

Locations
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United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Siqing Fu, MD, PhD    713-792-4318    siqingfu@mdanderson.org   
Contact: Katherine Torres    (832)750-4997    ktorres4@mdanderson.org   
Sub-Investigator: Robert C. Bast, MD         
Sub-Investigator: Amir A. Jazaeri, MD         
Sponsors and Collaborators
Green3Bio, Inc.
Investigators
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Principal Investigator: Siqing Fu, MD, PhD M.D. Anderson Cancer Center
More Information
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Responsible Party: Green3Bio, Inc.
ClinicalTrials.gov Identifier: NCT04711161    
Other Study ID Numbers: GRN300-001
First Posted: January 15, 2021    Key Record Dates
Last Update Posted: January 15, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Fallopian Tube Neoplasms
Ovarian Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Fallopian Tube Diseases
Adnexal Diseases
Endocrine Gland Neoplasms
Ovarian Diseases
 Endocrine System Diseases
Gonadal Disorders
Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action