Clinical Trials /

ONC201 and Paclitaxel in Treating Patients With Platinum-Resistant Refractory or Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

NCT04055649

Description:

This phase II trial studies the side effects of ONC201 and paclitaxel and how well they work in treating patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer that has come back (recurrent), or that does not respond to treatment (refractory). ONC201 is the first in its class of drugs that antagonize some specific cell receptors on cancer cells, leading to their destruction. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ONC201 and paclitaxel may work better in treating patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer compared to paclitaxel alone.

Related Conditions:
  • Fallopian Tube Carcinoma
  • Ovarian Carcinoma
  • Primary Peritoneal Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: ONC201 and Paclitaxel in Treating Patients With Platinum-Resistant Refractory or Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
  • Official Title: Phase II Study of ONC201 Plus Weekly Paclitaxel in Patients With Platinum-Resistant Refractory or Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Clinical Trial IDs

  • ORG STUDY ID: 2018-126
  • NCT ID: NCT04055649

Conditions

  • Malignant Ovarian Epithelial Tumor
  • Platinum-Resistant Fallopian Tube Carcinoma
  • Platinum-Resistant Ovarian Carcinoma
  • Platinum-Resistant Primary Peritoneal Carcinoma
  • Recurrent Fallopian Tube Carcinoma
  • Recurrent Ovarian Carcinoma
  • Recurrent Primary Peritoneal Carcinoma
  • Refractory Fallopian Tube Carcinoma
  • Refractory Ovarian Carcinoma
  • Refractory Primary Peritoneal Carcinoma

Interventions

DrugSynonymsArms
Akt/ERK Inhibitor ONC201ONC201, TIC10Treatment - ONC201 & Paclitaxel
PaclitaxelEster, Anzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol Konzentrat, Alpha, BetaTreatment - ONC201 & Paclitaxel

Purpose

This phase II trial studies the side effects of ONC201 and paclitaxel and how well they work in treating patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer that has come back (recurrent), or that does not respond to treatment (refractory). ONC201 is the first in its class of drugs that antagonize some specific cell receptors on cancer cells, leading to their destruction. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ONC201 and paclitaxel may work better in treating patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer compared to paclitaxel alone.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the safety and tolerability of the combination of Akt/ERK inhibitor ONC 201
      (ONC201) and paclitaxel in patients with platinum refractory or resistant epithelial ovarian,
      fallopian tube or primary peritoneal cancer. (Part 1) II. To evaluate the objective response
      rate (ORR) of ONC201 in combination with paclitaxel in patients with platinum refractory or
      resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. (Part 2) III. To
      evaluate progression free survival (PFS) of ONC201 in combination with weekly paclitaxel in
      patients with platinum refractory or resistant epithelial ovarian, fallopian tube or primary
      peritoneal cancer. (Part 2)

      SECONDARY OBJECTIVES:

      I. To evaluate the durability/duration of response (DOR) of ONC201 in combination with
      paclitaxel.

      II. To evaluate the safety and patient reported tolerability of ONC201 in combination with
      paclitaxel. (Part 2) III. To evaluate the disease control rate (DCR) of ONC201 in combination
      with paclitaxel.

      IV. To evaluate the cancer antigen-125 (CA-125) and/or human epididymis factor 4 (HE-4)
      response of ONC201 in combination with paclitaxel in those patients with one or both of these
      tumor markers upregulated.

      V. To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of ONC201 in
      combination with paclitaxel.

      VI. To obtain preliminary estimates of overall survival (OS) of ONC201 in combination with
      weekly paclitaxel.

      EXPLORATORY OBJECTIVES:

      I. To evaluate the immune response (specifically natural killer [NK] cell and cytokine
      profile) of ONC201 in combination with paclitaxel in patients with platinum refractory or
      resistant epithelial ovarian, fallopian tube or primary peritoneal cancer.

      OUTLINE:

      Patients receive ONC201 orally (PO) on days 1, 8, and 15, and paclitaxel intravenously (IV)
      over 1 hour on days 2, 9, and 16. Cycles repeat every 28 days in the absence disease
      progression or unacceptable toxicity. If paclitaxel must be stopped for any reason, patients
      may continue on ONC201 alone.

      After completion of study treatment, patients are followed up for 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment - ONC201 & PaclitaxelExperimentalPatients receive ONC201 PO on days 1, 8, and 15, and paclitaxel IV over 1 hour on days 2, 9, and 16. Cycles repeat every 28 days in the absence disease progression or unacceptable toxicity. If paclitaxel must be stopped for any reason, patients may continue on ONC201 alone.
  • Akt/ERK Inhibitor ONC201
  • Paclitaxel

Eligibility Criteria

        Inclusion Criteria:

          -  Histologic diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal
             cancer.

          -  Progressed within 6 months of completing at least 1 cycle of last platinum containing
             regimen. Patients with refractory disease (progression during platinum-containing
             therapy) are eligible. This includes both adjuvant therapy and in the recurrent
             setting.

          -  No more than 4 prior treatment regimens defined as investigational, chemotherapy,
             hormonal, biologic, or targeted therapy. Prior maintenance therapy with biologic or
             targeted agent does NOT count as a treatment regimen (e.g. maintenance bevacizumab,
             Parpi, or immunotherapy).

          -  At least one measurable lesion according to Response Evaluation Criteria in Solid
             Tumors (RECIST) version (v)1.1.

          -  For the eight patients enrolled for PK/PD. Availability of tissue from carcinoma. For
             most patients this will be archival tissue. If there is no archival tissue available,
             biopsy of lesion MUST be performed prior to initiation of therapy. Lesions must be
             available for biopsy as well in these patients.

          -  Any prior palliative radiation therapy must be completed at least 7 days prior to
             start of study treatment and patients must have recovered from any acute adverse
             effects prior to start of study treatment.

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-1.

          -  Female patients who are not of childbearing potential and fertile female patients of
             childbearing potential who agree to use adequate contraceptive measures from 2 weeks
             prior to the study and until 1 month after study treatment discontinuation, who are
             not breastfeeding, and who have a negative serum or urine pregnancy test within 3 days
             prior to start of study treatment.

          -  Absolute neutrophil count (ANC) >= 1,500/uL.

          -  Platelets >= 100,000/uL.

          -  Hemoglobin > 8.0 gm/dL.

          -  Calculated creatinine clearance (CrCl) >= 35 mL/min/1.73 mm^2.

          -  Bilirubin less than or equal to 1.5 x upper limit of normal (ULN).

          -  Alkaline phosphatase (AP), aspartate transaminase (AST) and alanine transaminase (ALT)
             less than or equal to 3 x ULN. AP, AST and ALT less than or equal to 5 x ULN is
             acceptable if patient has known hepatic metastasis.

        Exclusion Criteria:

          -  Use of a study drug (approved or investigational drug therapy) =< 21 days or 5
             half-lives (whichever is shorter) prior to the first dose of study treatment. For
             study drugs for which 5 half-lives is =< 21 days, a minimum of 10 days between
             termination of the study drug and administration of current study treatment is
             required.

          -  Major surgical procedures =< 21 days of beginning study treatment, or minor surgical
             procedures =< 7 days. No waiting required following port-a-cath placement, ureteral
             stent placement, percutaneous nephrostomy tube placement.

          -  No other (chemotherapy, immunotherapy, hormonal anti-cancer therapy, radiotherapy
             [except for palliative local radiotherapy]), biological therapy or other novel agent
             is to be permitted while the patient is receiving study medications.

          -  Grade > 1 toxicity from prior therapy (except alopecia or anorexia or above
             hematologic criteria) unless controlled by medications.

          -  Inability to swallow oral medication. Note: Patient may not have a percutaneous
             endoscopic gastrostomy (PEG) tube or be receiving total parenteral nutrition (TPN) on
             this trial.

          -  Known malignant central nervous system disease other than neurologically stable,
             treated brain metastases - defined as metastasis having no evidence of progression
             after treatment for at least 4 weeks (including brain radiotherapy). Must be off any
             systemic corticosteroids for the treatment of brain metastases for at least 14 days
             prior to enrollment.

          -  Patient has had prescription or non-prescription drugs or other products (i.e.
             grapefruit juice) known to be sensitive CYP3A4 substrates or CYP3A4 substrates with a
             narrow therapeutic index, or to be moderate to strong inhibitors or inducers of
             CYP3A4, which cannot be discontinued 1 week prior to day 1 of dosing and withheld
             throughout the study until 1 weeks after the last dose of study drug.

          -  Any known hypersensitivity or contraindication to the components of study treatment.

          -  Pregnant or lactating.

          -  Serious active infection at the time of enrollment, or another serious underlying
             medical condition at discretion of the enrolling physician that would impair the
             ability of the patient to receive study treatment. Human immunodeficiency virus (HIV)
             or other immunodeficiency disease that is well controlled and that does not impact
             baseline lab values (i.e. outside of above noted parameters for inclusion) are NOT
             considered exclusion criteria.

          -  Presence of other active cancers other than ovarian cancer except those that do not
             require active therapy (i.e. on surveillance) and known non-invasive cancers and in
             situ cancers (e.g. non-melanoma skin cancers).

          -  Psychological, familial, sociological, or geographical conditions that do not permit
             compliance with the protocol.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of treatment related adverse events (AEs) (Part 1)
Time Frame:Up to 28 days
Safety Issue:
Description:Graded according to National Cancer Institute (NCI) Common Terminology Criteria in Adverse Events (CTCAE) version (v)5.0.

Secondary Outcome Measures

Measure:Duration of response (DOR)
Time Frame:From first documented tumor response until the date of documented progression or death from any cause, assessed up to 1 year
Safety Issue:
Description:The distributions of additional time-to-event endpoints will be summarized using KM curves and their median and CI's will be further estimated using KM estimates.
Measure:Incidence of treatment related AEs
Time Frame:Up to 1 year
Safety Issue:
Description:Treatment emergent AEs and serious adverse events (SAEs) will be summarized by count and percentage per CTCAE v5.0.
Measure:Incidence of patient reported symptoms
Time Frame:Up to 1 year
Safety Issue:
Description:Will be summarized by count and percentage from the Functional Assessment of Cancer Therapy (FACT)-Taxane questionnaire. Repeated measured analysis of variance (ANOVA) will be conducted to assess for any changes in these symptoms by time. If a significant association with time is identified, pairwise comparisons between various time-points will be assessed using paired t-tests with a Tukey adjustment for multiple comparisons.
Measure:Disease clinical response (DCR)
Time Frame:At 6 months
Safety Issue:
Description:Defined as the proportion of patients achieving a complete response (CR), partial response (PR), or stable disease (SD) according to RECIST v1.1 criteria.
Measure:CA-125 response rate
Time Frame:Up to 1 year
Safety Issue:
Description:Defined as the proportion of patients achieving a 50% reduction in CA-125 levels from baseline, if baseline level is >= 2 x the upper limit of normal (ULN) within 2 weeks prior to starting treatment. Differences in these markers by response will be assessed by Fisher's exact tests, and difference in these markers over time will be assessed using McNemar's tests.
Measure:HE-4 response rate
Time Frame:Up to 1 year
Safety Issue:
Description:Defined as proportion of patients achieving a 50% reduction in HE-4 levels from baseline over time, if baseline level is >= 2 x ULN within 2 weeks prior to starting treatment, respectively. Differences in these markers by response will be assessed by Fisher's exact tests, and difference in these markers over time will be assessed using McNemar's tests.
Measure:Plasma concentrations of ONC201
Time Frame:Up to 1 year
Safety Issue:
Description:Examined to assess drug interactions with paclitaxel and characterize the pharmacokinetics (PK). PK parameters will be estimated using non-compartment or compartment models and summarized in mean and CIs under the assumption of log-normal distribution.
Measure:Pharmacodynamic studies
Time Frame:Up to 1 year
Safety Issue:
Description:As a biomarker of apoptosis, the serum cCK18 (M30 assay) and CK18 (M65 assay) will be used to quantify serum caspase-cleaved and total cytokeratin 18 levels. Prolactin levels will be assayed from the collected serum specimens. Repeated measured ANOVA will be conducted to assess for any changes in apoptosis and prolactin by time. If a significant association with time is identified, pairwise comparisons between various time-points will be assessed using paired t-tests with a Tukey adjustment for multiple comparisons. Tissue based biomarkers will be evaluated based on archival (pretreatment) and on-study biopsy tissue and compared via pre/post treatment H-score both within each individual patient and among the group of patients. Wilcoxon signed rank test will be used for pre/post comparisons.
Measure:Overall survival
Time Frame:From study treatment initiation to death, assessed up to 1 year
Safety Issue:
Description:The distributions of additional time-to-event endpoints will be summarized using KM curves and their median and CI's will be further estimated using KM estimates.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Ira Winer

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