Clinical Trials /

Sirolimus, Docetaxel, and Carboplatin in Treating Patients With Metastatic Castration-Resistant Prostate Cancer

NCT02565901

Description:

This partially randomized phase I/II trial studies the side effects and how well sirolimus works when given together with docetaxel and carboplatin in treating patients with castration-resistant prostate cancer that has spread to other places in the body (metastatic). Biological therapies, such as sirolimus, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop tumor cells from growing. Drugs used in chemotherapy, such as docetaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving sirolimus together with docetaxel and carboplatin may kill more tumor cells.

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Sirolimus, Docetaxel, and Carboplatin in Treating Patients With Metastatic Castration-Resistant Prostate Cancer
  • Official Title: A Phase 1-2 Study of Sirolimus, Docetaxel and Carboplatin for Treatment of Patients With Metastatic, Castration Resistant Prostate Cancer: (Rapamycin Inhibition of DDSP [RID])

Clinical Trial IDs

  • ORG STUDY ID: 9388
  • SECONDARY ID: NCI-2015-01478
  • SECONDARY ID: 9388
  • SECONDARY ID: P30CA015704
  • SECONDARY ID: P50CA097186
  • SECONDARY ID: RG1715104
  • NCT ID: NCT02565901

Conditions

  • Castration Levels of Testosterone
  • Castration-Resistant Prostate Carcinoma
  • Metastatic Prostate Carcinoma
  • Prostate Carcinoma Metastatic in the Bone
  • PSA Level Greater Than or Equal to Two
  • PSA Progression
  • Stage IV Prostate Cancer AJCC v7

Interventions

DrugSynonymsArms
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboArm I (sirolimus, docetaxel, carboplatin)
DocetaxelDocecad, RP56976, Taxotere, Taxotere Injection ConcentrateArm I (sirolimus, docetaxel, carboplatin)
SirolimusAY 22989, RAPA, Rapamune, Rapamycin, SILA 9268A, WY-090217Arm I (sirolimus, docetaxel, carboplatin)

Purpose

This partially randomized phase I/II trial studies the side effects and how well sirolimus works when given together with docetaxel and carboplatin in treating patients with castration-resistant prostate cancer that has spread to other places in the body (metastatic). Biological therapies, such as sirolimus, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop tumor cells from growing. Drugs used in chemotherapy, such as docetaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving sirolimus together with docetaxel and carboplatin may kill more tumor cells.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To define the recommended phase 2 dose (RP2D) of sirolimus combined with docetaxel and
      carboplatin in the treatment of metastatic castration resistant prostate cancer (CRPC).
      (Phase I)

      II. To assess the effectiveness of sirolimus in suppressing the induction of the
      deoxyribonucleic acid (DNA) damage secretory component WNT16B in tumor stroma following
      docetaxel and carboplatin. (Phase II)

      EXPLORATORY OBJECTIVES:

      I. To assess maximal prostate-specific antigen (PSA) response to sirolimus combined with
      docetaxel and carboplatin. (Phase I)

      II. To assess PSA response duration to sirolimus combined with docetaxel and carboplatin.
      (Phase I)

      III. To assess response of measurable disease. (Phase I)

      IV. To assess time to progression of bone lesions or measurable disease (Response Evaluation
      Criteria in Solid Tumors [RECIST] 1.1). (Phase I)

      V. To assess effect of sirolimus with docetaxel and carboplatin on DNA damage surrogates in
      cancer associated stroma compared to untreated and docetaxel and carboplatin treated stroma.
      (Phase I)

      VI. To assess maximal PSA response to sirolimus combined with docetaxel and carboplatin.
      (Phase II)

      VII. To assess PSA response duration to sirolimus combined with docetaxel and carboplatin.
      (Phase II)

      VIII. To assess response of measurable disease (RECIST 1.1). (Phase II)

      IX. To assess time to progression of bone lesions or measurable disease (RECIST 1.1). (Phase
      II)

      X. To assess toxicity of the RP2D dose of sirolimus with docetaxel and carboplatin. (Phase
      II)

      XI. To determine the effect of docetaxel and carboplatin therapy on the DNA damage secretory
      program (DDSP) in serum. (Phase II)

      XII. To determine response to sirolimus, docetaxel and carboplatin in tumors with mutation of
      DNA repair pathway genes (breast cancer gene 2 [BRCA2], ataxia telangiectasia mutated [ATM]
      and other Fanconi anemia complementation groups [FANC] pathway members). (Phase II)

      XIII. To correlate the presence of DNA repair pathway mutations in circulating tumor cells
      (CTC) and circulating tumor DNA (ctDNA) with tumor biopsy and correlate changes in CTC number
      and ctDNA mutation levels with clinical responses. (Phase II)

      OUTLINE: This is a phase I, dose de-escalation study of sirolimus followed by a phase II
      study.

      PHASE I: Patients receive sirolimus orally (PO) on day -2*. Patients also receive docetaxel
      intravenously (IV) over 30-60 minutes and carboplatin IV over 30-60 minutes on day 1.
      Treatment repeats every 21 days for 10 cycles in the absence of disease progression or
      unacceptable toxicity.

      PHASE II: Patients are randomized to 1 of 2 treatment arms.

      ARM I: Patients receive docetaxel IV over 30-60 minutes and carboplatin IV over 30 minutes on
      day 1. Beginning in course 2 and continuing in subsequent courses, patients also receive
      sirolimus PO on day -2. Treatment repeats every 21 days for 10 cycles in the absence of
      disease progression or unacceptable toxicity.

      ARM II: Patients receive sirolimus PO on day -2. Patients also receive docetaxel IV over
      30-60 minutes and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days
      for 10 cycles in the absence of disease progression or unacceptable toxicity.

      * NOTE: Patients receive sirolimus 2 days prior to chemotherapy day 1 (there is no day 0).
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (sirolimus, docetaxel, carboplatin)ExperimentalPatients receive docetaxel IV over 30-60 minutes and carboplatin IV over 30 minutes on day 1. Beginning in course 2 and continuing in subsequent courses, patients also receive sirolimus PO on day -2. Treatment repeats every 21 days for 10 cycles in the absence of disease progression or unacceptable toxicity.
  • Carboplatin
  • Docetaxel
  • Sirolimus
Arm II (sirolimus, docetaxel, carboplatin)ExperimentalPatients receive sirolimus PO on day -2. Patients also receive docetaxel IV over 30-60 minutes and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 10 cycles in the absence of disease progression or unacceptable toxicity.
  • Carboplatin
  • Docetaxel
  • Sirolimus

Eligibility Criteria

        Inclusion Criteria:

          -  Signed informed consent form (ICF) providing agreement to adhere to the dosing
             schedule, report for all trial visits and authorization, use and release of health and
             research trial information

          -  Histologically or cytologically confirmed carcinoma of the prostate (excluding
             neuroendocrine differentiation or squamous cell histology)

          -  Ongoing gonadal androgen deprivation therapy with gonadotropin-releasing hormone
             (GnRH) analogues, antagonists or orchiectomy; patients who have not had an orchiectomy
             must be maintained on effective GnRH analogue/antagonist therapy

          -  Castration resistant prostate cancer as defined by serum testosterone < 50 ng/ml and
             at least one of the following:

               -  PSA level of at least 2 ng/ml that has risen on at least 2 successive occasions
                  at least 1 week apart

               -  Evaluable disease progression by modified RECIST 1.1

               -  Progression of metastatic bone disease on bone scan with > 2 new lesions

          -  Prior therapy with abiraterone, enzalutamide and/or docetaxel; if a patient has not
             received docetaxel or cabazitaxel chemotherapy, the patient must be informed of this
             treatment choice as an alternative; if the patient has received docetaxel or
             cabazitaxel chemotherapy or refuses one of both of these therapies, this rationale
             must be documented and the patient is then eligible; patient must be offered and made
             aware of all Food and Drug Administration (FDA)‐approved treatment options; patients
             with bone only disease may not have received radium-223

          -  The presence of metastatic disease amenable to computed tomography (CT) or ultrasound
             guided biopsy; this may include thoracolumbar vertebral bodies, pelvis, femur or
             humerus or soft tissue or nodal metastasis amenable to biopsy (excluding lung or
             pleural lesions)

          -  Agree to participate in biopsy of metastatic lesion during the study at day 21

          -  Eastern Cooperative Oncology Group (ECOG) performance status of =< 1

          -  Life expectancy >= 12 weeks

          -  No prior malignancy is allowed except:

               -  Adequately treated basal cell or squamous cell skin cancer or

               -  In situ carcinoma of any site or

               -  Other adequately treated malignancy for which the patient is currently disease
                  free for at least one year

          -  Patients with any prior chemotherapy regimens are eligible

          -  Patients with disease only in the bone may not have received Xofigo/radium 223 to
             avoid ongoing DNA damage in bone marrow

          -  Patients who are or are not receiving bisphosphonates or denosumab are eligible;
             bisphosphonates or denosumab should not be initiated after registration and during
             active treatment

          -  Within 14 days prior to registration: Absolute neutrophil count >= 1.5 x 10^9 cells/L

          -  Within 14 days prior to registration: Hemoglobin (Hgb) >= 9.0 g/dL

          -  Within 14 days prior to registration: Platelets >= 100,000 x 10^9/L

          -  Within 14 days prior to registration: Aspartate aminotransferase (AST) and alanine
             aminotransferase (ALT) =< 1.5 x upper limit of normal (ULN)

          -  Within 14 days prior to registration: Total bilirubin =< 1.5 x ULN

          -  Within 14 days prior to registration: Serum creatinine < 1.5 X institutional ULN mg/dL
             OR estimated glomerular filtration rate (eGFR) >= 50 mL/min

        Exclusion Criteria:

          -  Patients currently receiving active therapy for other neoplastic disorders

          -  Patients with histologic evidence of small cell carcinoma of the prostate will not be
             eligible

          -  Patients with disease only in the bone previously treated with radium-223 will not be
             eligible

          -  Known parenchymal brain metastasis

          -  Active or symptomatic viral hepatitis or chronic liver disease

          -  Estimated creatinine clearance less than 50 ml/minute

          -  Clinically significant heart disease as evidenced by myocardial infarction, or
             arterial thrombotic events in the past 6 months, severe or unstable angina, or New
             York Heart Association (NYHA) class II-IV heart disease

          -  Atrial fibrillation, or other cardiac arrhythmia requiring medical therapy

          -  Administration of an investigational therapeutic within 30 days of cycle 1, day -2

          -  Patients with dementia/psychiatric illness/social situations that would limit
             compliance with study requirements or would prohibit the understanding and/or giving
             of informed consent

          -  Patients with medical conditions, which, in the opinion of the investigators, would
             jeopardize either the patient or the integrity of the data obtained will not be
             eligible

          -  Any condition which, in the opinion of the investigator, would preclude participation
             in this trial

          -  Patients on anticoagulation therapy which cannot be held for metastatic biopsies
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage change in deoxyribonucleic acid (DNA) damage secretory program induction (DDSP) (Phase II)
Time Frame:Baseline up to day 21 after starting treatment
Safety Issue:
Description:Will be determined by the level of genetic expression of WNT16, IL6, or SFRP2 in tissue after chemotherapy (carboplatin/docetaxel) compared to background/baseline measurement. The primary metric of DDSP induction will be quantitative reverse transcription-polymerase chain reaction, which is quantitative, but in the event of ribonucleic acid degradation in sample processing, the alternative measure will be immunohistochemistry (0-2 scale of expression).

Secondary Outcome Measures

Measure:Percentage of patients with reduction in prostate specific antigen according to the Prostate Cancer Working Group 2 (PCWG2) criteria (Phases I and II)
Time Frame:Baseline to up to 3 years
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Washington

Last Updated