A Study to Evaluate Safety/Tolerability of Immunotherapy Combinations in Participants With Triple-Negative Breast Cancer or Gynecologic Malignancies

Study Overview
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Brief Summary
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This is a Phase 1/1b, open-label, dose-escalation, and dose-expansion study to evaluate the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and clinical activity of etrumadenant (AB928) in combination with pegylated liposomal doxorubicin (PLD) with or without IPI-549 in participants with advanced metastatic triple-negative breast cancer (TNBC) or ovarian cancer, and etrumadenant in combination with nanoparticle albumin-bound-paclitaxel (NP) in participants with advanced metastatic TNBC.

Detailed Description
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In the dose escalation phase, the following will be assessed: Arm A: escalating doses of etrumadenant in combination with PLD at standard doses will be assessed in participants with advanced metastatic triple-negative breast cancer or ovarian cancer. Eligible participants will receive oral administration of etrumadenant as well as intravenous (IV) infusion of PLD. The recommended dose (RDE) for expansion Arms 1 and 2 and escalation Arm C will be determined upon completion of this dose escalation arm. Arm B: escalating doses of etrumadenant in combination with the NP at standard doses will also be assessed in participants with advanced metastatic TNBC. Eligible participants will receive oral administration of etrumadenant as well as NP infusion. The RDE of etrumadenant will be determined upon completion of this dose escalation arm. Arm C: escalating doses of IPI-549 in combination with the RDE of etrumadenant (from Arm A) and PLD at standard doses will be assessed in participants with advanced metastatic TNBC or ovarian cancer. Eligible participants will receive oral administration of both etrumadenant and IPI-549 as well as IV infusion of PLD. The RDE of IPI-549 for expansion Arm 4 will be determined upon completion of this dose escalation arm. In the dose expansion phase, the following will be assessed: Arms 1 and 2: Etrumadenant at the RDE in combination with PLD at standard doses may be assessed in participants with advanced metastatic TNBC or ovarian cancer. Arm 3: Etrumadenant at the RDE in combination with NP at standard doses may be assessed in participants with advanced metastatic TNBC. Arm 4: Etrumadenant and IPI-549 at the RDE in combination with PLD at standard doses may be assessed in participants with advanced metastatic TNBC. Overall duration of treatment will depend on how well the treatment is tolerated. Treatment may continue until unacceptable toxicity or progressive disease or other reasons specified in the protocol.

Official Title
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A Phase 1/1b Study to Evaluate the Safety and Tolerability of Immunotherapy Combinations in Participants With Breast or Gynecologic Malignancies

Conditions
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TNBC - Triple-Negative Breast Cancer, Ovarian Cancer

Intervention / Treatment
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* Drug: Etrumadenant
* Drug: IPI-549
* Drug: Pegylated liposomal doxorubicin (PLD)
* Drug: nanoparticle albumin-bound paclitaxel (NP)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female participants, 18 years or older Measurable disease per radiographic evaluation Performance status 0 or 1 Available archival tissue sample (within 2 years) or a fresh tumor biopsy may be required Adequate organ, cardiac, and bone marrow function Dose escalation Participants with breast cancer: Locally advanced or metastatic triple negative breast cancer (ER-negative, PgR-negative, and HER2-negative according to ASCO/CAP guidelines) with disease progression No available alternative or curative therapy Participants may have received any number of prior therapies for advanced/recurrent and progressive disease Participants with ovarian cancer: Locally advanced or metastatic ovarian cancer with disease progression No available alternative or curative therapy Participants may have received any number of prior therapies for advanced/recurrent and progressive disease Dose expansion Participants with breast cancer: Locally advanced or metastatic triple negative breast cancer (ER-negative, PgR-negative, and HER2-negative according to ASCO/CAP guidelines) Disease progression after no more than 3 prior lines of therapy Participants with ovarian cancer: Locally advanced or metastatic ovarian cancer that is platinum-resistant Disease progression after no more than 3 prior lines of therapy Exclusion Criteria: Received a live, attenuated vaccine within 4 weeks prior to first study treatment Prior anticancer treatment including approved agents, systemic radiotherapy, or investigational therapy within 4 weeks prior first study treatment Cancer other than the disease under study within 2 years prior to study entry, except for some cancers with a low risk of spreading like non-melanoma skin cancers Inability to swallow oral medications Participant is breastfeeding, pregnant, or expects to become pregnant during the study Active autoimmune disease or documented history of autoimmune disease within 2 years prior to first study treatment History of peptic ulcer or stomach bleeding within 6 months prior to first study treatment Use of drugs contraindicated by the protocol within 4 weeks prior to and during study treatment Prior treatment with drugs that suppress the immune system within 2 weeks prior to first study treatment Presence of metastases in the brain or cancer spreading into the cerebrospinal fluid - CSF (leptomeningeal disease) HIV, Hepatitis B, and C test results negative prior to first study treatment Major surgery within 4 weeks prior to first study treatment Participants who have previously received maximum cumulative lifetime anthracycline dosage or baseline ejection fraction <50% (on heart echography)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: 3+3 dose escalation
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation-Arm A<br>Dose escalation is a 3+3 design, including a Dose Limiting Toxicity (DLT) evaluation period. | Drug: Etrumadenant<br>* Etrumadenant is an A2aR and A2bR antagonist for oral use<br>* Other names: AB928;Drug: Pegylated liposomal doxorubicin (PLD)<br>* Doxil is an anthracycline topoisomerase II inhibitor that is encapsulated in liposomes for intravenous (IV) use<br>|
| Experimental: Dose Escalation-Arm B<br>Dose escalation is a 3+3 design, including a Dose Limiting Toxicity (DLT) evaluation period. | Drug: Etrumadenant<br>* Etrumadenant is an A2aR and A2bR antagonist for oral use<br>* Other names: AB928;Drug: nanoparticle albumin-bound paclitaxel (NP)<br>* NP is a microtubule inhibitor for intravenous (IV) use<br>|
| Experimental: Dose Escalation-Arm C<br>Dose escalation is a 3+3 design, including a Dose Limiting Toxicity (DLT) evaluation period. | Drug: Etrumadenant<br>* Etrumadenant is an A2aR and A2bR antagonist for oral use<br>* Other names: AB928;Drug: IPI-549<br>* IPI-549 is a phosphoinositide-3-kinase-gamma inhibitor for oral use<br>Drug: Pegylated liposomal doxorubicin (PLD)<br>* Doxil is an anthracycline topoisomerase II inhibitor that is encapsulated in liposomes for intravenous (IV) use<br>|
| Experimental: Dose Expansion-TNBC-Arm 1<br>The dose given will be determined from the dose escalation part (Arm A). | Drug: Etrumadenant<br>* Etrumadenant is an A2aR and A2bR antagonist for oral use<br>* Other names: AB928;Drug: Pegylated liposomal doxorubicin (PLD)<br>* Doxil is an anthracycline topoisomerase II inhibitor that is encapsulated in liposomes for intravenous (IV) use<br>|
| Experimental: Dose Expansion-Ovarian Cancer-Arm 2<br>The dose given will be determined from the dose escalation part (Arm A). | Drug: Etrumadenant<br>* Etrumadenant is an A2aR and A2bR antagonist for oral use<br>* Other names: AB928;Drug: Pegylated liposomal doxorubicin (PLD)<br>* Doxil is an anthracycline topoisomerase II inhibitor that is encapsulated in liposomes for intravenous (IV) use<br>|
| Experimental: Dose Expansion-TNBC-Arm 3<br>The dose given will be determined from the dose escalation part (Arm B). . | Drug: Etrumadenant<br>* Etrumadenant is an A2aR and A2bR antagonist for oral use<br>* Other names: AB928;Drug: nanoparticle albumin-bound paclitaxel (NP)<br>* NP is a microtubule inhibitor for intravenous (IV) use<br>|
| Experimental: Dose Expansion-TNBC-Arm 4<br>The dose expansion will be determined from the dose escalation part (Arm C). | Drug: Etrumadenant<br>* Etrumadenant is an A2aR and A2bR antagonist for oral use<br>* Other names: AB928;Drug: IPI-549<br>* IPI-549 is a phosphoinositide-3-kinase-gamma inhibitor for oral use<br>Drug: Pegylated liposomal doxorubicin (PLD)<br>* Doxil is an anthracycline topoisomerase II inhibitor that is encapsulated in liposomes for intravenous (IV) use<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events (AEs) |  | From first dose date to 30 days after the last dose (Approximately 1 year) | 
| Incidence of dose-limiting toxicities (DLTs) during the dose escalation phase |  | From first dose date to 28 days after the first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentration of etrumadenant |  | Recorded at baseline (prior to first dose), during the first 4 cycles of treatment (4 months) and at the end of treatment (i.e. in total approximately 5 months) | 
| Plasma concentration of IPI-549 |  | Recorded at baseline (prior to first dose), during the first 4 cycles of treatment (4 months) and at the end of treatment (i.e. in total approximately 5 months) | 
| Percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR), as determined by Investigator according to Response Evaluation in Solid Tumors (RECIST) v 1.1 |  | From study enrollment until participation discontinuation, first occurrence of progressive disease or death from any cause, whichever occurs first (approximately 3-5 years) | 
| Percentage of participants with Disease Control (complete response, partial response, or stable disease) for > 6 months as determined by RECIST v1.1 |  | From study enrollment until disease progression or loss of clinical benefit (up to approximately 3-5 years) | 
| Duration of Response as determined by the Investigator according to RECIST v1.1 |  | From the date of the first occurrence of a documented objective response to first documentation of disease progression or death from any cause, whichever occurs first (up to approximately 3-5 years) | 
| Progression Free Survival (PFS) as determined by the Investigator according to RECIST v1.1 |  | From start of the treatment up to first occurrence of progressive disease or death from any cause, whichever occurs first (up to approximately 3-5 years) | 
| Overall Survival (OS) as determined by the Investigator according to RECIST v1.1 |  | From start of treatment up to death from any cause (up to approximately 3-5 years) | 
| Percentage of etrumadenant target inhibition in peripheral blood |  | Cycle 1 Day 1 through Cycle 4 Day 1 (4 months) and at the end of treatment (in total approximately 5 months) | 
| Immunophenotyping activity in select immune subsets for etrumadenant and IPI-549 in peripheral blood |  | Cycle 1 Day 1 through Cycle 4 Day 1 (4 months) and at the end of treatment (in total approximately 5 months). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Triple Negative Breast Cancer, TNBC, Ovarian Cancer