Phase I/II Trial Investigating the Safety, Tolerability, Pharmacokinetics, Immune and Clinical Activity of SX-682 in Combination With BinTrafusp Alfa (M7824 or TGF-beta "Trap"/PD-L1) With CV301 TRICOM in Advanced Solid Tumors (STAT)

Phase 1

Completed

Conditions: Solid Tumors
Metastatic Cancer

Interventions: Drug: SX-682
Drug: M7824
Biological: MVA-BN-CV301
Biological: recombinant fowlpox viral (FPV)-CV301

Registration Number: NCT04574583

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Background:

Combination immunotherapy techniques are being explored to improve responses and enhance benefits in people with cancer. Researchers want to see if this type of treatment can help people with advanced solid tumors.

Objective:

To find a safe dose of SX-682 in combined treatment with Bintrafusp alfa and BN-CV301 vaccines and to see if this treatment will cause tumors to shrink.

Eligibility:

Adults age 18 and older with metastatic cancer may be eligible for the first part of the trial. Adults age 18 and older with metastatic triple negative breast cancer or p16 negative head and neck squamous cell cancer, and who are not candidates for curative surgery may be eligible for the second part of the trial.

Design:

Participants will be screened under a separate protocol.

Participants may have tumor biopsies. They will have physical exams. Their symptoms and medicines will be reviewed. They will have blood tests. They will have electrocardiograms to evaluate their heart.

Participants will have imaging scans of the chest, abdomen, and pelvis. They may have a procedure where a small tube with a tiny video camera is put into the nose to look at the throat if they have head and neck cancers.

Participants will get bintrafusp alfa through an intravenous catheter. For this, a small tube is put into an arm vein. They will get BN-CV301 vaccines as injections in the arm or thigh. They will take SX-682 by mouth twice a day. They will take the study drugs up to 2 years. They will keep a medicine diary.

Participants will have study visits every 2 weeks. They will have 1 or 2 follow-up visits within 30 days after they stop treatment. Then they will be monitored by phone or email for 2 years.

Detailed Description: Background:

* Combination immunotherapy approaches are being actively explored to further improve responses, enhance clinical benefit, and overcome resistance to Programmed Cell Death Ligand 1 (PD(L)-1) agents in cancer participants.

* Interleukin-8 (IL-8) is a pro-inflammatory chemokine produced by various cell types. Overexpression of IL-8 and/or its receptors C-X-C motif chemokine receptor 1 (CXCR1) and C-X-C motif chemokine receptor 2 (CXCR2), is commonly seen in many human cancers including breast, cervical, melanoma and prostate.

* SX-682 is an oral, small molecule inhibitor of the CXCR1/2 chemokine receptors that are believed involved in myeloid-derived suppressor cells (MDSC)-recruitment to tumor and other pro-tumoral mechanisms.

* Bintrafusp alfa (M7824 or MSB0011359C) is a bifunctional protein composed of the extracellular domain of the Transforming Growth Factor Beta Receptor 2 (TGF-BetaRII) receptor (TGF-Beta 'trap') fused to a human immunoglobulin G1 (IgG1). Preclinical data shows bintrafusp alfa treatment increases T-cell trafficking, antigen specific cluster of differentiation 8 (CD8+) T-cell lysis and natural killer (NK) cell activation.

* CV301 is a poxviral-based vaccine comprised of recombinant Modified vaccinia Ankara (MVA-BN-CV301, prime) and recombinant fowlpox (FPV-CV301, boost). CV301 contains transgenes encoding two (2) tumor-associated antigens (TAA), mucin 1 (MUC1) and carcinoembryonic antigen (CEA), as well as three costimulatory molecules (B7.1, intercellular adhesion molecule 1 (ICAM-1) and lymphocyte function-associated antigen 3 (LFA-3), designated TRICOM). A recent phase 1 clinical trial demonstrated that antigen-specific T cells to MUC1 and CEA, as well as to a cascade antigen, brachyury, were generated in most participants.

* Preclinical studies performed in LTIB with SX-682, M7824 and a CEA-based vaccine showed a significant reduction in tumor growth as well as a significant increase in tumor infiltration with cluster of differentiation 4 (CD4+) and CD8+ T cells.

Objectives:

* Arm 1 (Sequential Dose Escalation):

* To evaluate the safety and tolerability of single agent SX-682 given for 2 weeks preceding M7824 and CV301.

* To determine the maximum tolerated dose (MTD) of SX-682 given for 2 weeks preceding M7824 and the CV301 vaccines in participants with advanced or metastatic solid tumors. If the MTD is not reached the study will be focused to describe the safety and tolerability of SX-682 followed by M7824 and CV301 vaccines.

* Arm 2 (Combination Dose Escalation):

--To determine the recommended phase 2 dose (RP2D) of SX-682 given concurrently with M7824 and the CV301 vaccines in participants with advanced or metastatic solid tumors. If the MTD is not reached the study will be focused to describe the safety and tolerability of the drug combination.

* Arm 3 (Expansion):

* To evaluate preliminary efficacy based on Objective Response Rate (ORR), in each disease separately in two cohorts: Triple Negative Breast Cancer (TNBC) and Human papilloma virus (HPV) negative head and neck squamous cell carcinoma (HNSCC).

Eligibility:

* Age \>= 18 years old

* Arms 1 and 2 (Dose-Escalation Cohort): Subjects with cytologically or histologically confirmed locally advanced or metastatic solid tumors.

* Arm 3 (Expansion Cohorts):

* Triple Negative Breast Cancer (TNBC): Subjects with cytologically or histologically confirmed locally advanced or metastatic Triple Negative Breast Cancer that has progressed on at least one prior treatment in the advanced or in the metastatic setting.

* Human papilloma virus (HPV) negative head and neck squamous cell carcinoma (HNSCC): Subjects with cytologically or histologically confirmed locally advanced or metastatic, HPV negative head and neck squamous cell cancer (p16 negative for oropharyngeal) that has progressed on at least one prior treatment involving a platinum drug or cetuximab in advanced or in the metastatic setting.

* Prior first line systemic therapy is required unless there is no standard treatment available, the participant cannot tolerate standard first line treatment, or the participant declines standard treatment after appropriate counseling has been provided.

* Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1

* Adequate renal, hepatic, and hematologic function

* Subjects in Arms 1 and 2 may have disease that is measurable or non-measurable but evaluable disease (e.g. present on bone scan, rising tumor markers, non-measurable by Response Evaluation Criteria in Solid Tumors (RECIST) but visible on computed tomography (CT) scan). Participants with third space fluid (for example pleural effusions) as only site of disease will not be eligible. Subjects in Arm 3 must have measurable disease according to RECIST 1.1

Design:

* Arm 1 is a phase I, open-label, 3+3 sequential dose escalation trial with short term, 2-week SX-682 monotherapy, sequentially followed by treatment with M7824 and the CV301 vaccine series in advanced solid tumors (every 2 weeks (Q2W) dosing schedule) for the duration of treatment.

* Arm 2 is a phase I, open-label, 3+3 combination dose escalation trial with concurrently administered SX-682, M7824 and CV301 in advanced solid tumors (Q2W dosing schedule).

* Arm 3 has two expansion cohorts. Following identification of the MTD or recommended phase 2 dose (R2PD) for the combination of SX-682, M7824 and CV301 vaccine given concurrently, disease-specific phase 2 expansion cohorts will open in 1) advanced/metastatic triple negative breast cancer and 2) advanced/metastatic, platinum-refractory HPV negative head and neck squamous cell carcinoma.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 12

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase I Dose Level 3 (DL3) 100 mg SX-682 sequentially followed by 1200mg BinTraFusp Alfa +CV301	M7824	Participants with any solid tumor will receive a 2- week monotherapy lead-in of SX-682 DL1 100 mg by mouth (PO) twice a day (BID) followed sequentially by treatment with a dual combination of + BinTrafusp Alfa (M7824) 1200 mg fixed dose intravenous (IV) + BN-CV301. Participants will be evaluated for dose-limiting toxicities at the completion of the dose level before enrolling onto the next dose level.
Phase I Dose Level 2 (DL2) 50 mg SX-682 sequentially followed by 1200mg BinTraFusp Alfa + CV301	MVA-BN-CV301	Participants with any solid tumor will receive a 2- week monotherapy lead-in of SX-682 DL2 50 mg by mouth (PO) twice a day (BID) followed sequentially by treatment with a dual combination of + BinTrafusp Alfa (M7824) 1200 mg fixed dose intravenous (IV) + BN-CV301. Participants will be evaluated for dose-limiting toxicities at the completion of the dose level before enrollment to the next dose level begins
Phase I Dose Level 2 (DL2) 50 mg SX-682 sequentially followed by 1200mg BinTraFusp Alfa + CV301	M7824	Participants with any solid tumor will receive a 2- week monotherapy lead-in of SX-682 DL2 50 mg by mouth (PO) twice a day (BID) followed sequentially by treatment with a dual combination of + BinTrafusp Alfa (M7824) 1200 mg fixed dose intravenous (IV) + BN-CV301. Participants will be evaluated for dose-limiting toxicities at the completion of the dose level before enrollment to the next dose level begins
Phase I Dose Level 1(DL1) 25mg SX-682 monotherapy sequentially foll/by 1200mg BinTraFusp Alfa +CV301	SX-682	Participants with any solid tumor will receive a 2- week monotherapy lead-in of SX-682 DL2 50 mg by mouth (PO) twice a day (BID) followed sequentially by treatment with a dual combination of + BinTrafusp Alfa (M7824) 1200 mg fixed dose intravenous (IV) + BN-CV301. Participants will be evaluated for dose-limiting toxicities at the completion of the dose level before enrollment to the next dose level begins
Phase I Dose Level 1(DL1) 25mg SX-682 monotherapy sequentially foll/by 1200mg BinTraFusp Alfa +CV301	MVA-BN-CV301	Participants with any solid tumor will receive a 2- week monotherapy lead-in of SX-682 DL2 50 mg by mouth (PO) twice a day (BID) followed sequentially by treatment with a dual combination of + BinTrafusp Alfa (M7824) 1200 mg fixed dose intravenous (IV) + BN-CV301. Participants will be evaluated for dose-limiting toxicities at the completion of the dose level before enrollment to the next dose level begins
Phase I Dose Level 1(DL1) 25mg SX-682 monotherapy sequentially foll/by 1200mg BinTraFusp Alfa +CV301	recombinant fowlpox viral (FPV)-CV301	Participants with any solid tumor will receive a 2- week monotherapy lead-in of SX-682 DL2 50 mg by mouth (PO) twice a day (BID) followed sequentially by treatment with a dual combination of + BinTrafusp Alfa (M7824) 1200 mg fixed dose intravenous (IV) + BN-CV301. Participants will be evaluated for dose-limiting toxicities at the completion of the dose level before enrollment to the next dose level begins
Phase I Dose Level 1(DL1) 25mg SX-682 monotherapy sequentially foll/by 1200mg BinTraFusp Alfa +CV301	M7824	Participants with any solid tumor will receive a 2- week monotherapy lead-in of SX-682 DL2 50 mg by mouth (PO) twice a day (BID) followed sequentially by treatment with a dual combination of + BinTrafusp Alfa (M7824) 1200 mg fixed dose intravenous (IV) + BN-CV301. Participants will be evaluated for dose-limiting toxicities at the completion of the dose level before enrollment to the next dose level begins
Phase I Dose Level 3 (DL3) 100 mg SX-682 sequentially followed by 1200mg BinTraFusp Alfa +CV301	recombinant fowlpox viral (FPV)-CV301	Participants with any solid tumor will receive a 2- week monotherapy lead-in of SX-682 DL1 100 mg by mouth (PO) twice a day (BID) followed sequentially by treatment with a dual combination of + BinTrafusp Alfa (M7824) 1200 mg fixed dose intravenous (IV) + BN-CV301. Participants will be evaluated for dose-limiting toxicities at the completion of the dose level before enrolling onto the next dose level.
Phase I Dose Level 2 (DL2) 50 mg SX-682 sequentially followed by 1200mg BinTraFusp Alfa + CV301	recombinant fowlpox viral (FPV)-CV301	Participants with any solid tumor will receive a 2- week monotherapy lead-in of SX-682 DL2 50 mg by mouth (PO) twice a day (BID) followed sequentially by treatment with a dual combination of + BinTrafusp Alfa (M7824) 1200 mg fixed dose intravenous (IV) + BN-CV301. Participants will be evaluated for dose-limiting toxicities at the completion of the dose level before enrollment to the next dose level begins
Phase I Dose Level 3 (DL3) 100 mg SX-682 sequentially followed by 1200mg BinTraFusp Alfa +CV301	SX-682	Participants with any solid tumor will receive a 2- week monotherapy lead-in of SX-682 DL1 100 mg by mouth (PO) twice a day (BID) followed sequentially by treatment with a dual combination of + BinTrafusp Alfa (M7824) 1200 mg fixed dose intravenous (IV) + BN-CV301. Participants will be evaluated for dose-limiting toxicities at the completion of the dose level before enrolling onto the next dose level.
Phase I Dose Level 3 (DL3) 100 mg SX-682 sequentially followed by 1200mg BinTraFusp Alfa +CV301	MVA-BN-CV301	Participants with any solid tumor will receive a 2- week monotherapy lead-in of SX-682 DL1 100 mg by mouth (PO) twice a day (BID) followed sequentially by treatment with a dual combination of + BinTrafusp Alfa (M7824) 1200 mg fixed dose intravenous (IV) + BN-CV301. Participants will be evaluated for dose-limiting toxicities at the completion of the dose level before enrolling onto the next dose level.
Phase I Dose Level 2 (DL2) 50 mg SX-682 sequentially followed by 1200mg BinTraFusp Alfa + CV301	SX-682	Participants with any solid tumor will receive a 2- week monotherapy lead-in of SX-682 DL2 50 mg by mouth (PO) twice a day (BID) followed sequentially by treatment with a dual combination of + BinTrafusp Alfa (M7824) 1200 mg fixed dose intravenous (IV) + BN-CV301. Participants will be evaluated for dose-limiting toxicities at the completion of the dose level before enrollment to the next dose level begins

Primary Outcome Measures

Name	Time	Method
Recommended Phase II Dose (RP2D) of SX-682 With BinTrafusp Alfa (M7824) and CV301 Vaccines in Participants With Advanced or Metastatic Solid Tumors.	Approximately 28 days	Recommended phase II dose is defined as the dose defined in the phase I portion of a study that will be administered to participants on the phase II portion.
Percentage of Participants Who Experience a Response	11 months	The percentage of participants who experience a response will be reported along with 95% two-sided confidence intervals. The objective response is the best overall response recorded from the start of treatment until disease progression/recurrence per the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Stable Disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study.
Dose Limiting Toxicities (DLT)	DLT observation period (first 4 weeks)	A DLT is defined as any one of the following adverse events (AEs), as defined by Common Terminology Criteria for Adverse Events (CTCAE v5.0), that is possibly attributable to study drugs by the Investigator, that occur within 28 days after the start of study therapy: Any Grade 4 (life threatening) AEs, except for example, laboratory values that are determined to not be clinically significant or single laboratory valued that resolve to Grade ≤ 1 or baseline grade within 7 days with adequate medical management. Average corrected QT interval by Fridericia (QTcF)≥ 501 msec or \> 60 msec change from baseline (Grade 3). Any Grade 3 (severe) AEs except for example, Grade 3 flu-like symptoms or fever, as well as associated symptoms of fatigue, headaches, nausea, emesis which can be controlled with conservative medical management. Any grade 3 or higher adverse event or unexpected toxicities due to the combination of therapies that would not be expected with individual agents alone.
Maximum Tolerated Dose (MTD) of SX-682 Followed by BinTrafusp Alfa (M7824) and CV301 Vaccines in Participants With Advanced or Metastatic Solid Tumors.	Period of Safety lead-in (monotherapy), approximately 28 days	The MTD is the dose at which no more than 1 of 6 subjects taking SX-682 followed by M7824 and CV301 vaccines experience a dose-limiting toxicity (DLT). A DLT is defined as any one of the following adverse events (AEs), as defined by Common Terminology Criteria for Adverse Events (CTCAE v5.0), that is possibly attributable to study drugs by the Investigator, that occur within 28 days after the start of study therapy.
Number of Participants With Grades 3-5 Adverse Events (AEs) Related and/or Unrelated to SX-682 + BinTrafusp Alfa (M7824) + BN-CV301	Approximately 16 months and 11 days	Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to AE.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants Disease Control Rate (DCR): Complete Response (CR)+ Partial Response (PR) + Stable Disease (SD)	Date first participant enrolled and ending on the off treatment date of the last participant on treatment (i.e., assessed beyond the primary completion date), approximately 15 months and 14 days.	The percentage of participants disease control rate (DCR): Complete response (CR)+ partial response (PR) + stable disease (SD) was measured by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response is disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Stable Disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).
Progression-free Survival (PFS) Using Response Evaluation Criteria in Solid Tumors (RECIST)1.1.	Time from start of treatment to time of progression or death, whichever occurs first, approximately 10 months	PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progression per the RECIST is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions.
Pharmacokinetic Profile of SX-682 as a Single Agent and in Combination	Predose, 30 minutes, 60 minutes, 120 minutes, <6 hours of 2nd dose, and end of infusion (EOI)	Plasma and serum samples will be drawn and may be analyzed by a validated immunoassay to quantitate SX-682 as a single agent and in combination or by a validated electrochemiluminescence immunoassay to detect the presence of M7824 concentration.
Pharmacodynamic Profile of SX-682 as a Single Agent and in Combination	Predose, 30 minutes, 60 minutes, 120 minutes, <6 hours of 2nd dose, and end of infusion (EOI)	Plasma and serum samples will be drawn and may be analyzed by a validated immunoassay to quantitate SX-682 as a single agent and in combination or by a validated electrochemiluminescence immunoassay to detect the presence of M7824 concentration.