Clinical Trials /

Safety, Pharmacodynamics, Pharmacokinetics, and Efficacy of Tomivosertib Combined With Paclitaxel in Advanced Breast Cancer

NCT04261218

Description:

This is a multicenter, open-label trial to evaluate the safety, pharmacodynamics (PD), pharmacokinetics (PK), and efficacy of tomivosertib in combination with paclitaxel in patients with advanced breast cancer (ABC) of any subtype. The trial will enroll up to 45 patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2 with any breast cancer (BC) subtype and at least one measurable lesion, for whom standard-of-care treatments are ineffective, not tolerated or were refused. All patients will be initially treated with tomivosertib for 14 days (referred as the run-in period). Once treatment samples are obtained, weekly paclitaxel will be added to the treatment regimen. Tumor assessments will be done at screening and then periodically throughout trial treatment. Patients will continue to receive trial treatment until progressive disease, as defined according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, intolerable trial-treatment-related toxicity, consent withdrawal, or other criteria is met (defined within the trial protocol).

Related Conditions:
  • Breast Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Safety, Pharmacodynamics, Pharmacokinetics, and Efficacy of Tomivosertib Combined With Paclitaxel in Advanced Breast Cancer
  • Official Title: A Trial to Assess the Safety, Pharmacodynamic Effects, Pharmacokinetics and Efficacy of the MNK Inhibitor Tomivosertib (eFT508) in Combination With Paclitaxel, Following a Run-in Period of Tomivosertib Monotherapy, in Patients With Advanced Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: TRIO036
  • NCT ID: NCT04261218

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
tomivosertibeFT508Group 1 - Dose Finding
paclitaxelGroup 1 - Dose Finding

Purpose

This is a multicenter, open-label trial to evaluate the safety, pharmacodynamics (PD), pharmacokinetics (PK), and efficacy of tomivosertib in combination with paclitaxel in patients with advanced breast cancer (ABC) of any subtype. The trial will enroll up to 45 patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2 with any breast cancer (BC) subtype and at least one measurable lesion, for whom standard-of-care treatments are ineffective, not tolerated or were refused. All patients will be initially treated with tomivosertib for 14 days (referred as the run-in period). Once treatment samples are obtained, weekly paclitaxel will be added to the treatment regimen. Tumor assessments will be done at screening and then periodically throughout trial treatment. Patients will continue to receive trial treatment until progressive disease, as defined according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, intolerable trial-treatment-related toxicity, consent withdrawal, or other criteria is met (defined within the trial protocol).

Trial Arms

NameTypeDescriptionInterventions
Group 1 - Dose FindingExperimentalThe first 3 patients enrolled in Group 1 will receive tomivosertib at a dose of 100 mg orally twice daily (BID), and will be assessed for dose limiting toxicities (DLTs) during this 'run-in' period. They will also receive the first cycle of tomivosertib IN COMBINATION with weekly paclitaxel in the 'post run-in' period. Depending on the occurrence/absence of DLTs, this first group of 3 patients may need to be expanded (up to 9 patients) or the trial may proceed to start enrollment in Group 2 (detailed in the arm below).
  • tomivosertib
  • paclitaxel
Group 2 - Dose ExpansionExperimentalIt is anticipated that Group 2 patients will receive tomivosertib at a dose of 200 mg orally twice daily (BID) during the 'run-in' period, which is taken in combination with weekly paclitaxel (according to market label) during the 'post run-in' period.
  • tomivosertib
  • paclitaxel

Eligibility Criteria

        Inclusion Criteria:

          1. Signed and dated Patient Informed Consent Form (PICF) obtained prior to any
             trial-specific screening procedure.

          2. Women or men aged ≥ 18 years-old on the day of the written informed consent is given.

          3. Histologically or cytologically confirmed breast adenocarcinoma that is either
             metastatic (stage IV of the TNM classification) or locally recurrent and not amenable
             to local curative treatment.

          4. Known ER, PgR and HER2 statuses (note: the BC subtype at trial entry will be
             determined by the statuses in the most recent sample(s) tested for ER, PgR and HER2).

          5. Evidence of measurable disease (according to RECIST v.1.1) based on imaging studies
             and/or physical examination.

          6. Patient is a candidate for weekly paclitaxel as palliative treatment for the locally
             recurrent and/or metastatic disease in the opinion of the treating physician, or is
             receiving paclitaxel but is no longer achieving disease control (note: any number of
             prior lines of standard-of-care or experimental therapies are allowed).

          7. At least one metastatic (or recurrent) lesion that is amenable to repeated biopsy and
             willingness and ability to undergo two biopsies (at screening and approximately 2
             weeks after the start of trial treatment).

          8. ECOG performance status of 0, 1 or 2.

          9. Life expectancy of ≥ 6 months per Investigator's judgement.

         10. Adequate organ function during screening, as defined below:

               -  Hemoglobin ≥8.0 g/dL (criterion must be met without erythropoietin dependency and
                  without packed red blood cell transfusion within the last 2 weeks)

               -  Absolute neutrophil count ≥1,500 cells/mm3

               -  Platelet count ≥100,000 cells/mm3

               -  Total bilirubin ≤1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ULN for
                  participants with total bilirubin levels >1.5 × ULN

               -  Aspartate aminotransferase and alanine aminotransferase ≤3 × ULN (≤5 × ULN for
                  patients with liver metastases)

               -  Measured or calculated creatinine clearance (CrCl) >60 mL/min (if calculated, it
                  should be done using the Cockcroft-Gault formula)

         11. For women of childbearing potential (WoCBP) - must meet all of the following criteria:

               -  Not pregnant (negative serum pregnancy within 14 days of enrollment), and

               -  Not breastfeeding, and

               -  Willing to use a protocol-recommended method of contraception (refer to details
                  within protocol), from the start of tomivosertib until at least 30 days after the
                  last dose of trial treatment.

             Note: A female patient is considered to be of childbearing potential unless she has
             had a hysterectomy, bilateral tubal ligation/occlusion, or bilateral oophorectomy, has
             medically documented ovarian failure (with serum estradiol and follicle-stimulating
             hormone levels within the institutional laboratory postmenopausal range), or is
             postmenopausal. Post-menopausal status is defined as 12 consecutive months with no
             menses without an alternative medical cause.

         12. For sexually active male subjects who can father a child - must be willing to refrain
             from sperm donation and to use a protocol-recommended method of contraception
             (detailed within protocol), from the start of tomivosertib until at least 74 days
             after the last dose of trial treatment.

         13. Willing and able to comply with the scheduled visits, drug administration plan,
             protocol-specified laboratory tests, other trial procedures, and trial restrictions.
             Note: psychological, social, familial, or geographical factors that might preclude
             adequate trial participation should be considered.

        Exclusion Criteria:

          1. Current evidence of incomplete recovery from clinically-significant toxicities
             associated with prior anti-cancer treatment(s), that would represent a
             contra-indication to experimental therapy in the opinion of the Investigator.

          2. Prior systemic standard or investigational anti-cancer therapy within 3 weeks prior to
             enrollment and/or major surgery within 2 weeks prior to enrollment.

          3. Known symptomatic brain metastases requiring ≥10 mg/day of prednisolone (or its
             equivalent). Patients with previously diagnosed brain metastases are eligible if they
             have completed their treatment, have recovered from the acute effects of radiation
             therapy or surgery prior to the start of tomivosertib, fulfill the steroid requirement
             and are neurologically stable.

          4. Active infection requiring systemic therapy.

          5. Gastrointestinal disease that may interfere with drug absorption or with
             interpretation of gastrointestinal adverse events (e.g., gastric or intestinal bypass
             surgery, pancreatic enzyme insufficiency, malabsorption syndrome, symptomatic
             inflammatory bowel disease, chronic diarrheal illness, bowel obstruction).

          6. Significant cardiovascular disease including myocardial infarction, arterial
             thromboembolism, or cerebrovascular thromboembolism, within 8 weeks prior to the start
             of tomivosertib; unstable dysrhythmias or other known clinically significant
             electrocardiogram abnormality; unstable angina; New York Heart Association Class 3 or
             4 congestive heart failure; uncontrolled hypertension (diastolic blood pressure ≥100
             mmHg and/or systolic blood pressure ≥180 mmHg); or history of congenital prolonged QT
             syndrome.

          7. Prior therapy with any inhibitor of MNK1 and/or MNK2.

          8. Use of a strong inhibitor or inducer of cytochrome P450 (CYP) 3A4 within 7 days prior
             to the start of tomivosertib or expected requirement for use of a strong CYP3A4
             inhibitor or inducer during trial treatment.

          9. Need for proton pump inhibitors or histamine H2 blockers at enrollment.

         10. Known or suspected hypersensitivity to the trial drugs or excipients contained in the
             trial drugs.

         11. History of another malignancy except for the following: adequately treated local basal
             cell or squamous cell carcinoma of the skin; in situ cervical carcinoma; adequately
             treated, papillary, noninvasive bladder cancer; other adequately treated malignancy
             currently in complete remission for ≥2 years.

         12. History or current evidence of any other medical or psychiatric condition or addictive
             disorder, or laboratory abnormality that, in the opinion of the Investigator, will
             increase the risks associated with trial participation, or require treatments that
             will interfere with the conduct of the trial or the interpretation of trial results.

         13. Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or
             breast-feed during her trial participation.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Patients with Adverse Events (AEs)
Time Frame:Every serious adverse event (SAE) and related AE, following informed consent and at least until the '30-day safety follow-up' visit, will be assessed. All AEs during treatment will also be included.
Safety Issue:
Description:The assessment of safety will be based mainly on the frequency of non-serious and serious AEs. The Medical Dictionary for Regulatory Activities will be used to code all AEs to a system organ class and a preferred term. Incidence of AEs will be tabulated by system organ class, preferred term and toxicity grade. Each of these outputs will include for each AE, system organ class and preferred term as reported by the Investigator based on Common Terminology Criteria for Adverse Events (NCI CTCAE). Detailed listings for all adverse events will also be provided.

Secondary Outcome Measures

Measure:Overall Response Rate (ORR)
Time Frame:Tumor assessments used to determine ORR will be conducted at screening and every 8 ± 2 weeks from the enrollment date for 12 months, then every 12 ± 2 weeks, until progressive disease, consent withdrawal, or death.
Safety Issue:
Description:ORR is defined as the proportion of patients who have a complete response or partial response according to RECIST v.1.1, based on the Investigator's assessment.
Measure:Clinical Benefit Rate (CBR)
Time Frame:Tumor assessments used to determine CBR will be conducted at screening and every 8 ± 2 weeks from the enrollment date for 12 months, then every 12 ± 2 weeks, until progressive disease, consent withdrawal, or death.
Safety Issue:
Description:CBR is defined as the proportion of patients who have a complete response or partial response or stable disease according to RECIST v.1.1, based on the Investigator's assessment.
Measure:Pharmacokinetic Effects (PK)
Time Frame:All patients from Group 1 and 5-8 patients from Group 2 will be considered as the PK subset. Plasma samples will be obtained at the pre-determined time points during cycle 2 - days 1 and 2. Following cycle 1, treatment cycles are 28 days.
Safety Issue:
Description:Plasma concentrations of tomivosertib and paclitaxel will be determined using validated liquid chromatography tandem-mass spectrometry assays. Plasma concentrations will be summarized by scheduled time point with descriptive statistics, which will include the n, mean, standard deviation, coefficient of variation (%), median, minimum, and maximum.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Translational Research in Oncology

Last Updated

December 17, 2020