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Palbociclib 125 mg daily + AntiHER2 Therapy (trastuzumab/pertuzumab) q3wks + Endocrine Therapy (letrozole, anastrozole, exemstane OR fulvestratnt) until confirmed disease progression

AntiHER2 Therapy (trastuzumab/pertuzumab) q3wks + Endocrine Therapy (letrozole, anastrozole, exemstane OR fulvestrant) until confirmed disease progression

o Starting dose: 125 mg capsule taken orally once per day for 21 days followed by 7 days off to complete 28 day cycle. Dose reductions: 100 mg, 75 mg. allowed. Number of Cycles: until progression or unacceptable toxicity develops

palbociclib

Patients must have received a minimum of 4 and maximum of 8 cycles of induction therapy prior to randomization to Arm A or B, at which point they will continue on antiHER2 therapy and endocrine therapy, with or without palbociclib. Trastuzumab dosing will be determined based on a loading dose of 8mg trastuzumab/kg body weight for Q3WK dosing schedules or a maintenance dose of 6mg/kg trastuzumab/kg dosing weight for Q3WK dosing schedules. Loading dose will be administered on Cycle 1, Day 1.

trastuzumab

Patients must have received a minimum of 4 and maximum of 8 cycles of induction therapy prior to randomization to Arm A or B, at which point they will continue on antiHER2 therapy and endocrine therapy, with or without palbociclib.Pertuzumab will be administered at a loading dose of 840 mg infusion and then at a maintenance dose of 420 mg q3wks. If patient is within 5 weeks of receiving loading dose at Cycle 1, Day 1, patient may start with maintenance dose of 420 mg.

pertuzumab

There are several allowed endocrine treatment agents for Arm A and Arm B of this study. Administration is performed on an outpatient, self-administration basis according to local requirements and local standard practice. Endocrine treatment may have started before the patient enters the study. Agents will be administered at the discretion of principal investigator as well as according to standard institutional or regional practice. Recommended dosing regimen for letrozole oral therapy is 2.5 mg orally, once a day.

letrozole

There are several allowed endocrine treatment agents for Arm A and Arm B of this study. Administration is performed on an outpatient, self-administration basis according to local requirements and local standard practice. Endocrine treatment may have started before the patient enters the study. Agents will be administered at the discretion of principal investigator as well as according to standard institutional or regional practice. Recommended dosing regimen for anastrozole is 1 mg orally, once a day.

There are several allowed endocrine treatment agents for Arm A and Arm B of this study. Administration is performed on an outpatient, self-administration basis according to local requirements and local standard practice. Endocrine treatment may have started before the patient enters the study. Agents will be administered at the discretion of principal investigator as well as according to standard institutional or regional practice. Recommended dosing regimen for exemestane is 25 mg orally, once a day.

There are several allowed endocrine treatment agents for Arm A and Arm B of this study. Administration is performed on an outpatient, self-administration basis according to local requirements and local standard practice. Endocrine treatment may have started before the patient enters the study. Agents will be administered at the discretion of principal investigator as well as according to standard institutional or regional practice. Recommended dosing regimen for Fulvestrant is 250 mg injections on Day 1 and Day 15 of Cycle 1, and q4weeks thereafter.

The primary objective of this study is to demonstrate that the combination of palbociclib with anti-HER2 therapy plus endocrine therapy is superior to anti-HER2-based therapy plus endocrine therapy alone in improving the outcomes of subjects with hormone receptor-positive, HER2+ metastatic breast cancer.

Subjects will be randomized into one of two treatment arms following minimum of 4 and maximum of 8 cycles of induction treatment with anti-HER2 therapy. Arm A subjects will receive the experimental therapy, palbociclib, in addition to their current anti-HER2 therapy and endocrine therapy. Arm B subjects will continue to receive the anti-HER2 therapy. It is expected that the addition of palbociclib to the first-line treatment of HER2 disease will delay the onset of therapeutic resistance and ultimately prolong the survival of patients with metastatic breast cancer. The study is designed to treat the subset of patients with HER2+ disease who are also hormone receptor positive (HR+). It is also expected that palbociclib will modulate the endocrine resistance in HER2+/HR+ disease and potentiate the benefits of anti-HER2 therapy. Lastly, the current study includes a comprehensive molecular characterization of the disease at study entrance which will allow us to investigate the benefits of palbociclib in subsets of HER2+/HR+ disease such as PIK3CA mutant.

Randomized, Open Label, Clinical Study of the Targeted Therapy, Palbociclib, to Treat Metastatic Breast Cancer

A Randomized, Open Label, Phase III Trial to Evaluate the Efficacy and Safety of Palbociclib + Anti-HER2 Therapy + Endocrine Therapy vs. Anti-HER2 Therapy + Endocrine Therapy After Induction Treatment for Hormone Receptor Positive (HR+)/HER2-Positive Metastatic Breast Cancer

Progression Free Survival (PFS) based upon investigator assessment of progression between patients in the two treatment arms in the subset of patients with tumors bearing a PIK3CA mutation.

Will evaluate baseline tumor and blood-based markers as predictors of benefit from the addition of palbociclib to anti-HER2 therapy plus endocrine therapy

Defined as time from date of randomization to date of death due to any cause

Survival probabilities will be estimated using the Kaplan-Meier method

Defined as complete response (CR) or partial response (PR) according to RECIST v1.1

Defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of objective tumor progression or to death from any cause, whichever occurs first

The Clinical Benefit Rate (CBR) on each treatment arm will be estimated by dividing the number of patients with CR, PR, or SD/Non-CR and Non-PD (for patients with measurable disease) ≥ 24 weeks by the number of patients randomized to the treatment arm.

Seriousness and attribution to the study medications of AEs and any laboratory abnormalities

Time to symptom progression (FACT-B PFB-TOI), breast cancer specific health treatment related quality of life and general health status

Compare the incidence of CNS metastasis between treatment arms

Pfizer

German Breast Group

Fondazione Michelangelo

PrECOG, LLC.

Breast Cancer Trials, Australia and New Zealand

Syneos Health

SOLTI Breast Cancer Research Group

UNICANCER

Alliance Foundation Trials, LLC.

Paclitaxel

Docetaxel

Albumin-Bound Paclitaxel

Capecitabine

Vinorelbine

Tubulin Modulators

Antimitotic Agents

Antimetabolites

Physician's choice of chemotherapy plus trastuzumab plus pertuzumab

* trastuzumab, given as a loading dose of 8 mg/kg intravenously (IV, or through the vein) on Day 1 followed by 6 mg/kg IV every 3 weeks thereafter, AND
* physician's choice of chemotherapy:

  1. Vinorelbine 25 mg/m2 IV weekly times 3 with 1 week off; OR
  2. Paclitaxel 80 mg/m2 IV weekly times 3 with 1 week off; OR
  3. Nab-Paclitaxel 100 mg/m2 IV weekly times 3 with 1 week off; OR
  4. Docetaxel 75 mg/m2 IV every 3 weeks; OR
  5. Capecitabine 1500 mg by mouth twice a day (PO BID) 14 days on and then 7 days off.
* AND pertuzumab given as a loading dose of 840 mg IV on Day 1 followed by 420 mg IV every 3 weeks.

Physician's choice of chemotherapy plus trastuzumab

* trastuzumab, given as a loading dose of 8 mg/kg intravenously (IV, or through the vein) on Day 1 followed by 6 mg/kg IV every 3 weeks thereafter, AND
* physician's choice of chemotherapy:

  1. Vinorelbine 25 mg/m2 IV weekly times 3 with 1 week off; OR
  2. Paclitaxel 80 mg/m2 IV weekly times 3 with 1 week off; OR
  3. Nab-Paclitaxel 100 mg/m2 IV weekly times 3 with 1 week off; OR
  4. Docetaxel 75 mg/m2 IV every 3 weeks; OR
  5. Capecitabine 1500 mg PO BID 14 days on and then 7 days off.

Treatment for all patients will consist of trastuzumab, given as a loading dose of 8 mg/kg IV on Day 1 followed by 6 mg/kg IV every 3 weeks thereafter.

Patients randomized to the chemotherapy plus trastuzumab arm (without pertuzumab) can receive trastuzumab 6 mg/kg IV every 3 weeks if they are receiving docetaxel or capecitabine on a 3-week cycle, or 4 mg/kg IV every 2 weeks if they are receiving vinorelbine, paclitaxel, or nab-paclitaxel on a 4-week cycle. The loading dose for all patients remains 8 mg/kg.

For patients randomized to the chemotherapy plus trastuzumab plus pertuzumab arm, both trastuzumab and pertuzumab need to be administered every 3 weeks regardless of which chemotherapy agent they are receiving.

pertuzumab given as a loading dose of 840 mg IV on Day 1 followed by 420 mg IV every 3 weeks.

physician's choice of chemotherapy:

* Vinorelbine 25 mg/m2 IV weekly times 3 with 1 week off; OR
* Paclitaxel 80 mg/m2 IV weekly times 3 with 1 week off; OR
* Nab-Paclitaxel 100 mg/m2 IV weekly times 3 with 1 week off; OR
* Docetaxel 75 mg/m2 IV every 3 weeks; OR
* Capecitabine 1500 mg by mouth twice a day (PO BID) 14 days on and then 7 days off.

Vinorelbine, Paclitaxel, Nab-Paclitaxel , Docetaxel, Capecitabine

Neelima Denduluri, MD

This randomized phase 2 study will seek to determine the effectiveness of chemotherapy (physician's choice of vinorelbine, taxane \[paclitaxel, docetaxel or nab paclitaxel\] or capecitabine) plus trastuzumab vs chemotherapy (physician's choice) plus trastuzumab plus pertuzumab in women with HER2-overexpressing metastatic breast (MBC) that has been previously treated with ado-trastuzumab emtansine (T-DM1) in the metastatic setting.

The current preferred first-line therapy for patients with HER2-overexpressing metastatic breast cancer (MBC) is a taxane plus trastuzumab plus pertuzumab, based on results from the CLEOPATRA trial. For patients with disease that has progressed on trastuzumab and a taxane, ado-trastuzumab emtansine (T-DM1) was recently approved based on results from the EMILIA trial showing superiority in this setting compared with capecitabine plus lapatinib. However, the standard for first-line therapy may change again in the near future, when results become available from the MARIANNE trial, which is evaluating T-DM1 alone or in combination with pertuzumab as upfront therapy. Two important questions that may be raised by the findings of this study are whether pertuzumab is effective as second- or later-line therapy following single-agent T-DM1, and whether pertuzumab administered beyond progression on prior pertuzumab therapy is of clinical benefit as trastuzumab has been proven to be.

The study will seek to determine the efficacy of chemotherapy (physician's choice of vinorelbine, taxane \[paclitaxel, docetaxel or nab paclitaxel\] or capecitabine) plus trastuzumab vs chemotherapy (physician's choice) plus trastuzumab plus pertuzumab in women with HER2-overexpressing MBC that has been previously treated with T-DM1 in the metastatic setting.

We hypothesize that the addition of pertuzumab to trastuzumab plus chemotherapy will improve median progression-free survival (PFS), compared to trastuzumab plus chemotherapy alone, as second- or later-line therapy in patients who have received prior T-DM1. Patients will be stratified according to whether they have received prior pertuzumab versus not. We will also explore whether continuing treatment with pertuzumab in patients who have been previously treated with pertuzumab improves PFS.

Phase 2 Study of Standard Chemotherapy With Trastuzumab, Plus or Minus Pertuzumab, for Pre-treated Metastatic Breast Cancer

Randomized Phase II Trial of Chemotherapy of Physician's Choice Plus Trastuzumab Versus Chemotherapy of Physician's Choice Plus Trastuzumab Plus Pertuzumab In Women With Pretreated, HER2-Overexpressing Metastatic Breast Cancer (MBC)

The primary objective of this study is to compare progression-free survival (PFS \[also known as time to disease progression\]) with the addition of pertuzumab to trastuzumab plus physician's choice of chemotherapy versus trastuzumab plus physician's choice of chemotherapy in patients who have previously received treatment with ado-trastuzumab emtansine (TDM1) for HER2+ metastatic breast cancer.

To assess PFS with the addition of pertuzumab to trastuzumab plus physician's choice of chemotherapy in patients who have received prior pertuzumab;

To compare median PFS with the addition of pertuzumab to trastuzumab plus physician's choice of chemotherapy in patients who have received 1 vs 2-3 prior chemotherapy regimens for metastatic disease;

To compare the objective response rates (ORR; complete response \[CR\] plus partial response \[PR\]) between the two treatment arms;

To assess overall survival (OS) in each of the treatment arms;

To assess the safety of pertuzumab in combination with trastuzumab and physician's choice of chemotherapy (vinorelbine, paclitaxel, nab-paclitaxel, docetaxel, or capecitabine).

Genentech, Inc.

US Oncology Research

Carcinoma

Taxane

Ricolinostat

Histone Deacetylase Inhibitors

Subject will receive ACY-1215 (ricolinostat) orally once daily for 21 consecutive days (Day 1 to Day 21) at the assigned dose, followed by a 7-day non-dosing period (Day 22 to Day 28). 100 mg/m2 Nab-paclitaxel will be administered intravenously on Days 1, 8, and 15.

An orally active, selective HDAC6 inhibitor. Assigned dosing 80 mg, 120 mg, 180 mg, 240 mg PO, once daily Days 1-21 in a 28-day cycle

ACY-1215

Taxanes are among the most widely used chemotherapy agents in the treatment of breast cancer.

100 mg/m2 30 minute IV infusion Days 1, 8, and 15 in a 28-day cycle

Nab-paclitaxel

Kevin Kalinsky, MD, MS

This is a non-randomized phase 1 trial designed to determine the MTD and evaluate the safety and tolerability of ACY-1215 with nab-paclitaxel. Based on the activity profile of ACY-1215 in breast cancer, corresponding biomarker availability with the HDAC6 MR score, and its potential synergy with taxanes, these data support the rationale for testing the ability of ACY-1215 to improve the response rate for patients with metastatic breast cancer in combination with standard taxane chemotherapy.

Breast cancer is the most common female cancer and the second most common cause of death in women. Women with hormone receptor-negative tumors that are associated with symptomatic visceral metastases, or hormone receptor-positive tumors that are refractory to endocrine therapy require cytotoxic chemotherapy for disease control. The standard of care for patients with metastatic breast cancer includes single agent taxane-based chemotherapy. Combination chemotherapy generally provides higher rates of objective response and longer time to progression, compared to single-agent chemotherapy. However, it is associated with increased toxicity and is of little survival benefit. There remains an unmet need for combination regimens incorporating new, effective and oftentimes less toxic targeted agents together with standard chemotherapy.

ACY-1215 + Nab-paclitaxel in Metastatic Breast Cancer

Multi-center Phase IB Trial of ACY-1215 (Ricolinostat) Combined With Nab-paclitaxel in Unresectable or Metastatic Breast Cancer

The maximum tolerated dose (MTD) combination is defined as the dose combination associated with a target probability of dose limiting toxicity (DLT) of 0.25. A dose-limiting toxicity is defined as the MTD with DLTs defined as any grade 3 non-hematologic toxicities despite maximal supportive care or any grade 4 hematologic toxicity. The MTD will be estimated using the time to event continual reassessment method (TITE-CRM). The TITE-CRM will use an empirical dose-toxicity model, with a sample size of 24. The dose-toxicity model is calibrated such that the method will eventually select a dose that yields between 17% and 33% DLT, which will be the recommended phase II dose (RP2D).

All patients will be evaluable for toxicity from the time of their first treatment with the study drug. Toxicities will be graded based upon CTCAE v4.0.2.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Randomized, Open Label, Clinical Study of the Targeted Therapy, Palbociclib, to Treat Metastatic Breast Cancer	NCT02947685	HER-2 Positive ... Estrogen Recept...	palbociclib trastuzumab pertuzumab letrozole Anastrozole Exemestane Fulvestrant	18 Years -	Alliance Foundation Trials, LLC.
Phase 2 Study of Standard Chemotherapy With Trastuzumab, Plus or Minus Pertuzumab, for Pre-treated Metastatic Breast Cancer	NCT02229149	Breast Neoplasm... Malignant Tumor...	Trastuzumab Pertuzumab Vinorelbine, Pa...	18 Years -	US Oncology Research
ACY-1215 + Nab-paclitaxel in Metastatic Breast Cancer	NCT02632071	Metastatic Brea... Breast Carcinom...	ACY-1215 Nab-paclitaxel	18 Years -	Columbia University
Phase 2 Study of Standard Chemotherapy With Trastuzumab, Plus or Minus Pertuzumab, for Pre-treated Metastatic Breast Cancer	NCT02229149	Breast Neoplasm... Malignant Tumor...	Trastuzumab Pertuzumab Vinorelbine, Pa...	18 Years -	US Oncology Research

Spots Global Cancer Trial Database for malignant tumor of the breast