A Study To Assess The Tolerability And Clinical Activity Of Gedatolisib In Combination With Palbociclib/Letrozole Or Palbociclib/Fulvestrant In Women With Metastatic Breast Cancer

Study Overview
=================
Brief Summary
-----------------
This is a multicenter, open label, Phase 1b study in patients with mBC. This study will have a dose escalation to identify the maximum tolerated dose (MTD) of the combination of gedatolisib plus palbociclib/fulvestrant and gedatolisib plus palbociclib/letrozole and expansion to estimate the objective response rate (OR) of the combination of gedatolisib plus palbociclib/letrozole or palbociclib/fulvestrant.

Detailed Description
-----------------
This is a multicenter, open label, continuous Phase 1b study in patients with MBC. This study will have a dose escalation and expansion. The dose escalation will identify the maximum tolerated dose (MTD) of the combination of gedatolisib plus palbociclib/fulvestrant and gedatolisib plus palbociclib/letrozole. The expansion will estimate the objective response rate (OR) of the combination of gedatolisib plus palbociclib/letrozole and the combination of gedatolisib plus palbociclib/fulvestrant.

Official Title
-----------------
PHASE 1B STUDY TO ASSESS THE SAFETY, TOLERABILITY, AND CLINICAL ACTIVITY OF GEDATOLISIB IN COMBINATION WITH PALBOCICLIB AND EITHER LETROZOLE OR FULVESTRANT IN WOMEN WITH METASTATIC OR LOCALLY ADVANCED/RECURRENT BREAST CANCER (MBC)

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: Gedatolisib
* Drug: Palbociclib
* Drug: Letrozole
* Drug: Fulvestrant


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Women 18 years of age or older, who are either: Postmenopausal or Pre/perimenopausal women with medically-induced menopause by treatment with agents to induce chemical menopause. Histologically or cytologically proven diagnosis of breast cancer with evidence of metastasis. Documentation of estrogen receptor positive ((ER+), human epidermal growth factor receptor 2 (HER2 negative (HER2-)) tumor. Dose Escalation Portion: Patients must satisfy one of the following criteria: Letrozole combination cohort (L): metastatic breast cancer (MBC) with progression who are candidates for a letrozole-containing regimen, with palbociclib. Fulvestrant combination cohort (F): MBC with progression who are candidates for a fulvestrant containing regimen, with palbociclib. Dose Expansion Portion: Patients must satisfy one of the following criteria: Arm A: MBC with progression and no prior endocrine based systemic therapy in the metastatic setting; Arm B: MBC with progression during or following one prior endocrine based systemic therapy in the metastatic setting, with no prior therapy with any cyclin-dependent kinase (CDK) inhibitor; Arm C/Arm D: MBC with progression during or following one or two prior endocrine based systemic therapies in the metastatic setting, and following prior therapy with a CDK inhibitor. Measurable disease as defined by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Bone only patients during dose escalation portion. Availability of archival tumor biopsy sample or willing to provide fresh biopsy if not available. Eastern Cooperative Oncology Group [ECOG] performance must be 0 or 1. Adequate bone marrow, renal and liver function. Exclusion Criteria: Prior treatment with a mechanistic target of rapamycin (mTOR) inhibitor or phosphoinositide 3-kinase (PI3K) inhibitor. More than 1 line of prior chemotherapy in the treatment of metastatic or locally advanced/recurrent disease. Bone only patients during expansion/efficacy portion. Patients with advanced/metastatic disease who have symptomatic visceral spread, and who have life threatening complications needing immediate therapy, such as massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and over 50% liver replacement with tumor. Known active uncontrolled or symptomatic Central Nervous System (CNS) metastases. Active bacterial, fungal or viral infection. Uncontrolled or significant cardiovascular disease. Radiation therapy within 4 weeks of investigational product. Cytotoxic chemotherapy within 4 weeks of investigational product (6 weeks for mitomycin C or nitrosoureas) if immediate prior regimen was administered on an every 3 4 week schedule or 2 weeks of investigational product if immediate prior regimen consisted of weekly therapy. Any other anti cancer agents (eg, hormonal, biological, investigational) within 5 times the half life prior to investigational product. Impairment of gastro intestinal (GI) function or GI disease. Pregnant female patients; breastfeeding female patients; and female patients of childbearing potential who are unwilling or unable to use 2 highly effective methods of contraception as outlined in this protocol for the duration of the study and for 90 days.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Letrozole Cohort<br>Letrozole combination cohort in dose escalation | Drug: Gedatolisib<br>* Gedatolisib weekly intravenous starting at 180 mg/week in a 4 week cycle.<br>Drug: Palbociclib<br>* Palbociclib initiated at 125 mg daily: 3 out of 4 weeks in a 4 week cycle.<br>Drug: Letrozole<br>* Letrozole at 2.5 mg daily<br>|
| Experimental: Fulvestrant cohort<br>Fulvestrant combination cohort in dose escalation | Drug: Gedatolisib<br>* Gedatolisib weekly intravenous starting at 180 mg/week in a 4 week cycle.<br>Drug: Palbociclib<br>* Palbociclib initiated at 125 mg daily: 3 out of 4 weeks in a 4 week cycle.<br>Drug: Fulvestrant<br>* Fulvestrant administered intramuscularly at 500 mg on Day 1, 15 and 28 and then every 28 days.<br>|
| Experimental: ARM A<br>Gedatolisib + palbociclib + letrozole in dose expansion | Drug: Gedatolisib<br>* Gedatolisib weekly intravenous starting at 180 mg/week in a 4 week cycle.<br>Drug: Palbociclib<br>* Palbociclib initiated at 125 mg daily: 3 out of 4 weeks in a 4 week cycle.<br>Drug: Letrozole<br>* Letrozole at 2.5 mg daily<br>|
| Experimental: ARM B<br>Gedatolisib + palbociclib + fulvestrant in dose expansion | Drug: Gedatolisib<br>* Gedatolisib weekly intravenous starting at 180 mg/week in a 4 week cycle.<br>Drug: Palbociclib<br>* Palbociclib initiated at 125 mg daily: 3 out of 4 weeks in a 4 week cycle.<br>Drug: Fulvestrant<br>* Fulvestrant administered intramuscularly at 500 mg on Day 1, 15 and 28 and then every 28 days.<br>|
| Experimental: ARM C<br>Gedatolisib + palbociclib + fulvestrant in dose expansion | Drug: Gedatolisib<br>* Gedatolisib weekly intravenous starting at 180 mg/week in a 4 week cycle.<br>Drug: Palbociclib<br>* Palbociclib initiated at 125 mg daily: 3 out of 4 weeks in a 4 week cycle.<br>Drug: Fulvestrant<br>* Fulvestrant administered intramuscularly at 500 mg on Day 1, 15 and 28 and then every 28 days.<br>|
| Experimental: Arm D<br>Gedatolisib (3:1) + palbociclib + fulvestrant in dose expansion | Drug: Fulvestrant<br>* Fulvestrant administered intramuscularly at 500 mg on Day 1, 15 and 28 and then every 28 days.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with dose limiting toxicities |  | up to 28 days | 
| Objective response rate observed in patients in the dose expansion portion | Number of patients for each response category, objective response rate (number of patients with a complete response (CR)) relative to the number of response evaluable patients | 16 weeks | 
| Objective response rate observed in patients in the dose expansion portion | Number of patients for each response category, objective response rate (number of patients with a partial response (PR)) relative to the number of response evaluable patients) | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor response observed in patients in the dose escalation portion |  | 16 weeks | 
| Duration of response |  | 16 weeks | 
| QTc interval (corrected QT interval) | The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. | Screening up to 6 months | 
| Maximum observed plasma concentration |  | Day 1: 0, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 24, 72 and 168 hours. Cycle 2 Day 1: 0, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 24, 72 and 168 hours | 
| Progression free survival |  | 16 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PI3K (phosphoinositide 3-kinase), mTOR (mechanistic target of rapamycin), PI3K/mTOR, metastatic breast cancer (MBC), ER+ (estrogen receptor positive), HER2- (human epidermal growth factor receptor 2 negative)