A Phase 1b Study of Paclitaxel And Ricolinostat For The Treatment Of Gynecological Cancer
Condition: Ovarian Cancer; Fallopian Tube Cancer; Primary Peritoneal Carcinoma
MeSH terms: Fallopian Tube Neoplasms
Intervention: Paclitaxel; Ricolinostat; Bevacizumab
Intervention description: Please see arm/group description.; Please see arm/group description.; Please see arm/group description.
Intervention MeSH terms: Paclitaxel; Bevacizumab; Ricolinostat
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Participants with Ovarian, Fallopian Tube, or Peritoneal Cancer that has recurred within 12
      months of prior treatment that includes Platinum Chemotherapy are invited to take part in
      this study. This research study is studying a combination of a new chemotherapy drug called
      Ricolinostat together with the chemotherapy Paclitaxel and a drug called Bevacizumab as a
      possible treatment for this diagnosis.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participants must have recurrent or persistent epithelial ovarian, fallopian tube or
             primary peritoneal carcinoma, recurrent endometrial cancer, or recurrent cervical
             cancer. Histologic documentation of the original primary tumor is required via the
             pathology report.

          -  Participants must have measurable disease by RECIST 1.1 criteria. See Section 11 for
             the evaluation of measurable disease.

          -  Participants must have had at least one prior platinum-based chemotherapeutic regimen
             for management of primary disease (e.g., a regimen containing carboplatin, cisplatin,
             or another organoplatinum compound). This initial treatment may have included
             intraperitoneal therapy, consolidation, biologic/targeted (non-cytotoxic) agents
             (e.g., bevacizumab) or extended therapy administered after surgical or non-surgical
             assessment.

        Participants are allowed to receive, but are not required to receive, biologic/targeted
        (non-cytotoxic) therapy as part of their primary treatment regimen.

          -  Participants must have recurrence within 12 months of their last platinum-containing
             regimen.

          -  Age 18 years or older

          -  ECOG performance status 0 or 1

          -  Life expectancy of greater than 16 weeks

          -  Participants must have normal organ and marrow function as defined below:

               -  Leukocytes ≥3,000/mcL

               -  Absolute neutrophil count ≥1,500/mcL

               -  Platelets ≥100,000/mcL

               -  Total bilirubin within normal institutional limits

               -  AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal

               -  Creatinine within normal institutional limits OR

               -  Creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels
                  above institutional normal.

          -  Previous toxicities from previous treatment must have resolved to grade 1 or less

          -  For patients in expansion cohort B, stable Grade 2 neuropathy will be allowed.

          -  The effects of both paclitaxel and oral ricolinostat on the developing human fetus are
             unknown. For this reason, women of child-bearing potential and men must agree to use
             adequate contraception (hormonal or barrier method of birth control; abstinence) prior
             to study entry and for the duration of study participation. Should a woman become
             pregnant or suspect she is pregnant while she or her partner is participating in this
             study, she should inform her treating physician immediately.

          -  Participants must be able and willing to swallow pills and to absorb oral medications.

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Participants must be able and willing to follow protocol instructions and schedules.

        Exclusion Criteria:

          -  Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to entering the study or those who have not
             recovered from adverse events due to agents administered more than 4 weeks earlier. In
             addition, no small molecule kinase inhibitors or any other type of investigational
             agent may have been administered within 4 weeks before first dose of study treatment.

          -  Participants may not be receiving any other investigational agents for treatment of
             their cancer.

          -  No hormonal therapy is allowed within 1 week of initiating study treatment.

          -  Participants may not have had radiation to >25% of the bone marrow.

          -  Prior treatment with a histone deacetylase inhibitor.

          -  Prior treatment with weekly paclitaxel for recurrent or persistent disease is not
             allowed. Participants may have received weekly paclitaxel as part of treatment for
             newly diagnosed cancer, but may not have received it as maintenance therapy following
             their initial therapy with platinum and taxane therapy.

          -  Participants with known brain metastases should be excluded from this clinical trial
             because of their poor prognosis and because they often develop progressive neurologic
             dysfunction that would confound the evaluation of neurologic and other adverse events.

          -  History of severe allergic reactions attributed to compounds of similar chemical or
             biologic composition to either paclitaxel or Ricolinostat. Patients who require
             administration of paclitaxel through a desensitization procedure are not eligible for
             this study.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements.

          -  Patients with chronic viral illnesses such as HIV-positivity and active hepatitis B or
             C are ineligible because they are at increased risk of lethal infections when treated
             with marrow-suppressive therapy.

          -  Any signs, symptoms, and/or radiographic evidence of a complete or partial bowel
             obstruction

          -  Patients with a history of other invasive malignancies, with the exception of
             non-melanoma skin cancer and other specific malignancies as noted below, are excluded
             if there is any evidence of other malignancy being present within the last three
             years. Patients are also excluded if their previous cancer treatment contraindicates
             this protocol therapy.

               -  Carcinoma in situ of the breast or cervix

               -  Primary endometrial cancer meeting the following conditions: Stage not greater
                  than IA, grade 1 or 2, no more than superficial myometrial invasion, without
                  vascular or lymphatic invasion; no poorly differentiated subtypes, including
                  papillary serous, clear cell, or other FIGO grade 3 lesions.

          -  Patients who have received prior chemotherapy for any abdominal or pelvic tumor OTHER
             THAN for the treatment of ovarian, fallopian tube, or primary peritoneal cancer within
             the last three years are excluded. Patients may have received prior adjuvant
             chemotherapy for localized breast cancer, provided that it was completed more than
             three years prior to registration, and the patient remains free of recurrent or
             metastatic disease.

          -  Patients with clinically significant cardiovascular disease. This includes:

               -  Uncontrolled hypertension, defined as systolic greater than 140 mm Hg or
                  diastolic greater than 90 mm Hg despite antihypertensive medications.

               -  Myocardial infarction or unstable angina within 6 months prior to registration.

               -  New York Heart Association (NYHA) Class II or greater congestive heart failure.
                  (see Appendix III )

               -  History of serious ventricular arrhythmia (i.e., ventricular tachycardia or
                  ventricular fibrillation) or serious cardiac arrhythmia requiring medication.
                  This does not include asymptomatic atrial fibrillation with controlled
                  ventricular rate.

               -  Any history of congenital long QT syndrome

               -  The subject has a corrected QT interval calculated by the Fridericia formula
                  (QTcF) >500 ms within 28 days before randomization. Note: if initial QTcF is
                  found to be > 500 ms, two additional EKGs separated by at least 3 minutes should
                  be performed. If the average of these three consecutive results for QTcF is ≤500
                  ms, the subject meets eligibility in this regard.

          -  Patients with serious non-healing wound, ulcer, or bone fracture within 28 days before
             registration

          -  Patients with history of organ transplant.

          -  Patients with active bleeding or pathologic conditions that carry high risk of
             bleeding, such as known bleeding disorder, coagulopathy, or tumor involving (in
             contact with, invading or encasing) major vessels.

          -  Gastrointestinal disorders, particularly those with potential risk of perforation or
             fistula formation including:

               -  Any of the following within 28 days of registration

               -  Intra-abdominal tumor/metastases invading GI mucosa

               -  Active peptic ulcer disease

               -  Inflammatory bowel disease (including ulcerative colitis and Crohn's disease),
                  diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis

               -  Malabsorption syndrome.

               -  Any of the following within 6 months of registration

               -  Abdominal fistula

               -  Gastrointestinal perforation

               -  Bowel obstruction or gastric outlet obstruction

               -  Note: Patients requiring drainage gastrostomy (e.g., PEG tube) and/or parenteral
                  hydration and/or nutrition are not eligible.

               -  Intraabdominal abscess.

               -  Note: Complete resolution of an intraabdominal abscess must be confirmed prior to
                  registration even if the abscess occurred more than 6 months prior to
                  registration.

          -  Patients with history or evidence upon physical examination of CNS disease, including
             primary brain tumor, seizures which are not controlled with non-enzyme inducing
             anticonvulsants, any brain metastases and/or epidural disease, or history of
             cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or
             subarachnoid hemorrhage within six months prior to the first date of study treatment.

          -  Major surgery within 3 months of the first dose of study drugs if there were no wound
             healing complications or within 6 months of the first dose of study drugs if there
             were wound complications.

          -  The following are additional exclusion criteria for patients enrolling in Expansion
             Cohort C:

          -  Uncontrolled blood pressure (>140/90). Patients should have a blood pressure of
             ≤140/90 taken by a medical professional within one week of starting on study

          -  Proteinuria >2+ on urinalysis

          -  Serosal involvement of the bowel that would render the patient at increased risk of
             gastrointestinal perforation