Clinical Trials /

T-VEC With Chemotherapy or Endocrine Therapy in Treating Participants With Metastatic, Unresectable, or Locoregionally Recurrent HER2- Negative Breast Cancer

NCT03554044

Description:

This phase Ib trials studies the side effects and how well talimogene laherparepvec works when given together with chemotherapy or endocrine therapy in treating patients with breast cancer that does not express the human epidermal growth factor receptor 2 (HER2) protein and has spread to other places in the body (metastatic), cannot be removed by surgery (unresectable), or has come back (recurrent). Biological therapies, such as talimogene laherparepvec, use substances made from living organisms that may attack specific tumor cells and stop them from growing or kill them. Chemotherapy drugs, such as nab-paclitaxel, gemcitabine, 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. Estrogen can cause the growth of breast cancer cells. Drugs used as endocrine therapy, such as letrozole, anastrozole, exemestane, tamoxifen or fulvestrant, may lessen the amount of estrogen made by the body or may may stop the growth of tumor cells by blocking estrogen from connecting to the cancer cells. Giving talimogene laherparepvec with chemotherapy or endocrine therapy may work better in treating patients with HER2-negative breast cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: T-VEC With Chemotherapy or Endocrine Therapy in Treating Participants With Metastatic, Unresectable, or Locoregionally Recurrent HER2- Negative Breast Cancer
  • Official Title: A Phase 1b Study of Talimogene Laherparepvec (T-VEC) in Combination With Chemotherapy or Endocrine Therapy in Patients With Metastatic, Unresectable, or Locoregionally Recurrent HER2-negative Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: 17753
  • SECONDARY ID: NCI-2018-00652
  • NCT ID: NCT03554044

Conditions

  • Anatomic Stage III Breast Cancer AJCC v8
  • Anatomic Stage IIIA Breast Cancer AJCC v8
  • Anatomic Stage IIIB Breast Cancer AJCC v8
  • Anatomic Stage IIIC Breast Cancer AJCC v8
  • Anatomic Stage IV Breast Cancer AJCC v8
  • Estrogen Receptor Positive
  • HER2/Neu Negative
  • Invasive Breast Carcinoma
  • Prognostic Stage III Breast Cancer AJCC v8
  • Prognostic Stage IIIA Breast Cancer AJCC v8
  • Prognostic Stage IIIB Breast Cancer AJCC v8
  • Prognostic Stage IIIC Breast Cancer AJCC v8
  • Prognostic Stage IV Breast Cancer AJCC v8
  • Recurrent Breast Carcinoma

Interventions

DrugSynonymsArms
AnastrozoleArimidex, ICI-D1033, ZD-1033Cohort II (talimogene laherparepvec, endocrine therapy)
ExemestaneAromasin, FCE-24304Cohort II (talimogene laherparepvec, endocrine therapy)
FulvestrantFaslodex, ICI 182,780, ZD9238Cohort II (talimogene laherparepvec, endocrine therapy)
LetrozoleCGS 20267, FemaraCohort II (talimogene laherparepvec, endocrine therapy)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratCohort I (talimogene laherparepvec, chemotherapy)
Talimogene LaherparepvecICP34.5-, ICP47-deleted Herpes Simplex Virus 1 (HSV-1) Incorporating the Human GM-CSF Gene, Imlygic, JS1 34.5-hGMCSF 47- pA-, T-VEC, OncoVEXGM-CSFCohort I (talimogene laherparepvec, chemotherapy)
TamoxifenNolvadexCohort II (talimogene laherparepvec, endocrine therapy)
Nab paclitaxelAbraxaneCohort I (talimogene laherparepvec, chemotherapy)
GemcitabineGemzarCohort I (talimogene laherparepvec, chemotherapy)
CarboplatinParaplatinCohort I (talimogene laherparepvec, chemotherapy)

Purpose

This phase Ib trials studies the side effects and how well talimogene laherparepvec works when given together with chemotherapy or endocrine therapy in treating patients with breast cancer that does not express the human epidermal growth factor receptor 2 (HER2) protein and has spread to other places in the body (metastatic), cannot be removed by surgery (unresectable), or has come back (recurrent). Biological therapies, such as talimogene laherparepvec, use substances made from living organisms that may attack specific tumor cells and stop them from growing or kill them. Chemotherapy drugs, such as nab-paclitaxel, gemcitabine, 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. Estrogen can cause the growth of breast cancer cells. Drugs used as endocrine therapy, such as letrozole, anastrozole, exemestane, tamoxifen or fulvestrant, may lessen the amount of estrogen made by the body or may may stop the growth of tumor cells by blocking estrogen from connecting to the cancer cells. Giving talimogene laherparepvec with chemotherapy or endocrine therapy may work better in treating patients with HER2-negative breast cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the safety and tolerability of intra-lesional talimogene laherparepvec
      injections in combination with chemotherapy or endocrine therapy in patients with metastatic,
      unresectable, or locoregionally recurrent HER2-negative breast cancer who have injectable
      sites of disease.

      SECONDARY OBJECTIVES:

      To evaluate the efficacy of talimogene laherparepvec in combination with chemotherapy or
      endocrine therapy in the study population

      OUTLINE: Patients are assigned to 1 of 2 cohorts.

      COHORT I (CHEMOTHERAPY): Patients receive talimogene laherparepvec intra-tumorally (IT) on
      day 1 of cycle 1, on days 1 and 15 of cycle 2, on day 8 of cycle 3, then on day 1 of
      subsequent cycles. Patients also receive paclitaxel or nab-paclitaxel intravenously (IV) over
      60 minutes on days 1, 8, and possibly 15, or gemcitabine IV over 30-60 minutes and
      carboplatin IV over 30-60 minutes on days 1 and 8. Cycles repeat every 21 days in the absence
      of disease progression or unacceptable toxicity.

      COHORT II (ENDOCRINE THERAPY): Patients receive talimogene laherparepvec IT every 2 weeks for
      the first 10 weeks and then every 3 weeks thereafter. Patients also receive letrozole orally
      (PO), anastrazole PO, exemestane PO, tamoxifen PO on days 1-28 or fulvestrant intramuscularly
      (IM) every 2 weeks for 3 doses then every 4 weeks for the subsequent cycles. Cycles repeat
      every 28 days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 30 days.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort I (talimogene laherparepvec, chemotherapy)ExperimentalPatients receive talimogene laherparepvec intra-tumorally (IT) every 2 weeks for the first 10 weeks and every 3 weeks thereafter along with one of the following chemotherapies: paclitaxel (IV), nab-paclitaxel IV, or gemcitabine / carboplatin IV. Cycles repeat every 21 days until disease progression or unacceptable toxicity
  • Paclitaxel
  • Talimogene Laherparepvec
  • Nab paclitaxel
  • Gemcitabine
  • Carboplatin
Cohort II (talimogene laherparepvec, endocrine therapy)ExperimentalPatients receive talimogene laherparepvec intra-tumorally (IT) every 2 weeks for the first 10 weeks and every 3 weeks thereafter along with letrozole PO, anastrazole PO, exemestane PO, tamoxifen PO on days 1-21 or fulvestrant IM every 2 weeks for 3 doses then every 4 weeks for the subsequent courses. Cycles repeat every 28 days until disease progression or unacceptable toxicity
  • Anastrozole
  • Exemestane
  • Fulvestrant
  • Letrozole
  • Talimogene Laherparepvec
  • Tamoxifen

Eligibility Criteria

        Inclusion Criteria:

          1. Women or men 18 years or older with metastatic or locoregionally recurrent
             HER2-negative breast cancer. Resectable disease allowed.

          2. Ability to understand and voluntarily sign informed consent prior to undergoing any
             study-related assessments or procedures, as well as adhere to the study visit schedule
             and other protocol requirements.

          3. Histologic or cytologic confirmation of invasive breast cancer that is HER2-negative
             by standard clinical criteria.

          4. Patients who will participate in the endocrine therapy cohort must have invasive
             breast cancer that is ER+ (>=1% ER staining by IHC).

          5. At least one accessible and injectable lesion (ie. breast, chest wall, skin nodule or
             mass, axillary or supraclavicular lymph node) of at least 1cm. (Ultrasound imaging may
             be used as clinically indicated. Injection must be able to be performed at the
             bedside).

          6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.

          7. Concomitant use of bisphosphonates, RANKL antibody, and ovarian suppression is
             allowed.

          8. Adequate organ function:

               -  Absolute neutrophil count (ANC) >= 1.5x109/L for chemotherapy cohort, and >=
                  1.0x109/L for endocrine therapy cohort

               -  Hemoglobin (Hgb) >= 9g/dL

               -  Platelets (plt) >= 100 x 109/L for chemotherapy cohort, and >=75, 000 for
                  endocrine therapy cohort

               -  aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=2.5 x Upper
                  Limit Normal (ULN). If liver metastases present <=5 x ULN allowed.

               -  Serum total bilirubin <= 1.5 x ULN or direct bilirubin <= 1.5 × ULN in patients
                  with well documented Gilbert's Syndrome

               -  Serum creatinine <= 1.5 x ULN, or 24-hr clearance >= 60ml/min

               -  International normalization ratio (INR) or prothrombin time (PT) or partial
                  thromboplastin time (PTT)/ activated partial thromboplastin time (aPTT) <= 1.5 x
                  ULN

          9. Females of child-bearing potential (FCBP) should have a negative urine or serum
             pregnancy test within 72 hours prior to enrollment. If urine test is positive or
             cannot be confirmed as negative, a serum pregnancy test will be required. FCBP must
             also be willing to adhere to acceptable forms of birth control (a physician-approved
             contraceptive method: tubal ligation; intra-uterine device; barrier contraceptive with
             spermicide; or vasectomized partner) during the study treatment and through 3 months
             after the last dose of talimogene laherparepvec.

        FCBP are defined as sexually mature women who:

          -  Have not undergone a hysterectomy (the surgical removal of the uterus) or bilateral
             oophorectomy (the surgical removal of both ovaries) or,

          -  Have not been naturally postmenopausal for at least 12 consecutive months (i.e. has
             had menses at any time during the preceding 12 consecutive months)

          -  Must be willing to practice abstinence or use effective contraception for a minimum of
             3 months following completion of study treatment (in addition to during study
             therapy).

        Exclusion Criteria:

          1. Any significant medical condition, laboratory abnormalities, which places the subject
             at unacceptable risk if he/she were to participate in the study.

          2. Any condition that confounds the ability to interpret data from the study.

          3. Patients must have recovered from side effects resulting from prior cancer-directed
             therapy to a level of grade 1 or less (unless deemed not clinically significant by
             study investigator).

          4. Symptomatic central nervous system metastases. Subjects with brain metastases that
             have been previously treated and are stable for 4 weeks after whole-brain radiotherapy
             (WBXRT) or 2 weeks after Stereotactic radiosurgery (SRS) are allowed. Patients must be
             stable off steroids for brain metastases for at least 7 days. Subjects with
             asymptomatic clinically insignificant brain metastases not requiring treatment are
             allowed. The exception does not include carcinomatous meningitis which is excluded
             regardless of clinical stability.

          5. Patients with leptomeningeal disease.

          6. History of symptomatic autoimmune disease or active autoimmune disease that has
             required systemic treatment in the 2 weeks prior to enrollment. Replacement therapy
             (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for
             adrenal or pituitary insufficiency, etc.) is not considered a form of systemic
             treatment.

          7. Evidence of immune suppression due to: a) known human immunodeficiency virus (HIV)
             infection or AIDS; b) known leukemia or lymphoma; c) those who require high dose
             steroids (>10 mg/day of prednisone or equivalent within 7 days prior to enrollment) or
             other immunosuppressive therapies (>2weeks); d) active hepatitis B or C; e) congenital
             or acquired cellular and/or humoral immune deficiency; f) other signs or symptoms of
             immune system suppression or concurrent opportunistic infection.

          8. Nab-paclitaxel arm: Grade 2 or higher neuropathy.

          9. Known history of: cardiac disease, heart failure or decreased left ventricular
             ejection fraction, significant clinical arrhythmias.

         10. Patients must not have received an investigational agent within 4 weeks or <= 5
             half-lives, whichever is shorter, prior to starting study treatment.

         11. Last dose of prior chemotherapy must be at least 2 weeks, and 2 weeks for targeted
             therapies, before first dose of study treatment. There is no required washout for
             endocrine therapy.

         12. Major surgery or radiation ≤ 2 weeks prior to starting study treatment or who have not
             recovered from side effects of surgery or radiation.

         13. Active herpetic skin lesions or prior complications of HSV-1 infection (e.g. herpetic
             encephalitis or keratitis).

         14. Lesions with underlying infection or clinically meaningful bleeding.

         15. Requires intermittent or chronic systemic (intravenous or oral) treatment with an
             antiherpetic drug (e.g. acyclovir), other than intermittent topical use. Patients
             requiring anti-herpetic prophylaxis during chemotherapy are excluded.

         16. Previous treatment with talimogene laherparepvec or any other oncolytic virus.

         17. Prior therapy with tumor vaccine.

         18. Received live vaccine within 28 days prior to enrollment.

         19. Known allergic reaction to talimogene laherparepvec, nab-paclitaxel, gemcitabine,
             carboplatin, aromatase inhibitors, tamoxifen, fulvestrant, or any of their components.
             An exception is made if the patient will not be receiving the offending
             agent/component (i.e. a patient who is allergic to nab-paclitaxel but will be
             receiving endocrine therapy is eligible).

         20. Patients on therapeutic anticoagulation that cannot be held around injections.

         21. Women who are pregnant or breast-feeding.

         22. FCBP who are unwilling to use acceptable method(s) of effective contraception during
             study treatment and through 3 months after the last dose of talimogene laherparepvec.

         23. Sexually active subjects and their partners unwilling to use a male or female latex
             condom to avoid potential viral transmission during sexual contact while on treatment
             and within 30 days after treatment with talimogene laherparepvec.

         24. Subjects who are unwilling to minimize exposure with his/her blood or other body
             fluids to individuals who are at higher risks for HSV 1 induced complications
             (immunosuppressed individuals, HIV positive individuals, pregnant women, or children
             under the age of 1 year) during talimogene laherparepvec treatment and through 30 days
             after the last dose of talimogene laherparepvec.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of patients with treatment-related toxicities by maximum observed grade
Time Frame:Up to 2.5 years
Safety Issue:
Description:Treatment-related toxicities will be assessed according to NCI CTCAE v4.03, for all patients who receive at least one dose of study treatment. The distribution for the maximum observed grade for each adverse event will be tabulated and reported with 95% confidence interval

Secondary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:Up to 2.5 years
Safety Issue:
Description:The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence per Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1. Patients with complete response (CR) or partial response (PR) will be counted as having an objective response
Measure:Response duration
Time Frame:Up to 2.5 years
Safety Issue:
Description:Defined as the time from initial response to the first documented tumor progression.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of California, San Francisco

Last Updated

December 17, 2020