Sarcoma
Conditions
Brief summary
This phase I/II trial studies the side effects and best dose of doxorubicin hydrochloride when given together with pembrolizumab and to see how well they work in treating patients with sarcoma that have spread to other parts of the body or that cannot be removed by surgery. Drugs used in chemotherapy, such as doxorubicin hydrochloride, 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. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving doxorubicin hydrochloride together with pembrolizumab may work better in treating patients with sarcoma.
Detailed description
PRIMARY OBJECTIVES: I. To assess the safety and tolerability of the combination of pembrolizumab and doxorubicin hydrochloride (doxorubicin) in patients with advanced soft tissue sarcoma (STS). II. To assess the clinical response rate of advanced soft tissue sarcoma (STS) patients receiving the combination of pembrolizumab and doxorubicin. SECONDARY OBJECTIVES: I. To explore the clinical activity of pembrolizumab in subjects with advanced STS with respect to time to response. II. To explore the clinical activity of pembrolizumab in subjects with advanced STS with respect to duration of response. III. To explore the clinical activity of pembrolizumab in subjects with advanced STS with respect to progression-free survival (PFS). IV. To explore the clinical activity of pembrolizumab in subjects with advanced STS with respect to overall survival. TERTIARY OBJECTIVES: I. To compare response rates between patients with high levels of PD-L1 expression with those who have PD-L1 absent. OUTLINE: This is a phase I, dose-escalation study of doxorubicin hydrochloride followed by a phase II study. Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and doxorubicin hydrochloride IV over 1-3 hours on day 1 of courses 2-7 only. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 12 weeks.
Interventions
DRUGDoxorubicin Hydrochloride
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
BIOLOGICALPembrolizumab
Given IV
Sponsors
National Cancer Institute (NCI)
Fred Hutchinson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Be willing and able to provide written informed consent/assent for the trial * Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 * Have metastatic or unresectable sarcoma * Have a performance status of 0 to 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale * Absolute neutrophil count (ANC) \>= 1,500/mcL (within 10 days of treatment initiation) * Platelets \>= 100,000/mcL (within 10 days of treatment initiation) * Hemoglobin \>= 9 g/dL (within 10 days of treatment initiation) or \>= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment) * Serum creatinine =\< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate \[GFR\] can also be used in place of creatinine or creatinine clearance \[CrCl\]) \>= 60 mL/min for subject with creatinine levels \> 1.5 X institutional ULN (within 10 days of treatment initiation) * Serum total bilirubin =\< 1.5 X ULN OR direct bilirubin =\< ULN for subjects with total bilirubin levels \> 1.5 ULN (within 10 days of treatment initiation) * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 X ULN OR =\< 5 X ULN for subjects with liver metastases (within 10 days of treatment initiation) * Albumin \>= 2.5 mg/dL (within 10 days of treatment initiation) * International normalized ratio (INR) or prothrombin time (PT) =\< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (within 10 days of treatment initiation) * Activated partial thromboplastin time (aPTT) =\< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (within 10 days of treatment initiation) * Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required * Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year * Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy * Ejection fraction \> 45% by either multi-gated acquisition scan (MUGA) scan or echocardiogram
Exclusion criteria
* Has prior treatment using an anthracycline * Has one of the following sarcoma subtypes where combining anthracyclines with other chemotherapies is established as the standard of care: osteosarcoma, Ewings sarcoma, embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma * Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment * Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment * Has a known history of active TB (bacillus tuberculosis) * Hypersensitivity to pembrolizumab or any of its excipients * Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =\< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier * Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =\< grade 1 or at baseline) from adverse events due to a previously administered agent * Note: Subjects with =\< grade 2 neuropathy are an exception to this criterion and may qualify for the study * Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy * Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer * Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability * Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); 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 * Has known history of, or any evidence of active, non-infectious pneumonitis * Has an active infection requiring systemic therapy * Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator * Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial * Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment * Has received prior therapy with an anti-programed death receptor 1 (PD-1), anti-PD-L1, anti-program death receptor ligand 2 (PD-L2) agent or anti-CTLA4 * Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) * Has known active hepatitis B (e.g., hepatitis B surface antigen \[HBsAg\] reactive) or hepatitis C (e.g., hepatitis C virus \[HCV\] ribonucleic acid \[RNA\] \[qualitative\] is detected) * Has received a live vaccine within 30 days of planned start of study therapy * Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of Doxorubicin Hydrochloride Plus Pembrolizumab According to the National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) Version 4.0 (Phase I) | Up to 42 days (6 weeks) | Defined as a dose limiting toxicity (DLT) in less than 2 of 6 subjects. Only Phase 1 subjects will be evaluated for MTD. |
| Objective Response Rate (ORR) (Phase II) | Up to 2 years | Evaluated per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT. Complete Response (CR) is a complete elimination of the tumor; Partial Response (PR) is 30% reduction. If a subject experienced a PR, this was required to be confirmed with a second scan at the next appropriate cycle. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | Up to 2 years | Duration of response is the mean time to progression for all subjects who responded. |
| Median Progression-free Survival (PFS) | Up to 2 years | The Kaplan-Meier method will be used to estimate median PFS. |
| Overall Survival (OS) | Up to 2 years | The Kaplan-Meier method will be used to estimate median OS. |
| Time to Response | Up to 2 years | Average time to response |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1, Part 1 Subjects received 45 mg/m2 doxorubicin plus 200 mg flat dose of pembrolizumab. | 3 |
| Phase 1, Part 2 Subjects received 75 mg/m2 doxorubicin + 200 mg flat dose of pembrolizumab. | 3 |
| Phase 2 Subjects received 75 mg/m2 doxorubicin + 200 mg flat dose pembrolizumab. | 31 |
| Total | 37 |
Baseline characteristics
| Characteristic | Phase 1, Part 1 | Phase 1, Part 2 | Phase 2 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 8 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 2 Participants | 23 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 4 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 2 Participants | 26 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 4 Participants | 5 Participants |
| Race (NIH/OMB) White | 3 Participants | 2 Participants | 22 Participants | 27 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 14 Participants | 15 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 17 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 0 / 3 | 15 / 31 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 31 / 31 |
| serious Total, serious adverse events | 1 / 3 | 2 / 3 | 13 / 31 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of Doxorubicin Hydrochloride Plus Pembrolizumab According to the National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) Version 4.0 (Phase I)
Defined as a dose limiting toxicity (DLT) in less than 2 of 6 subjects. Only Phase 1 subjects will be evaluated for MTD.
Time frame: Up to 42 days (6 weeks)
Population: Only Phase 1 subjects were evaluated for a Maximum Tolerated Dose (MTD) based off of Dose-Limiting Toxicities experienced per subject as defined in the protocol.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 Cohort 1 | Maximum Tolerated Dose (MTD) of Doxorubicin Hydrochloride Plus Pembrolizumab According to the National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) Version 4.0 (Phase I) | 0 Participants |
| Phase 1 Cohort 2 | Maximum Tolerated Dose (MTD) of Doxorubicin Hydrochloride Plus Pembrolizumab According to the National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) Version 4.0 (Phase I) | 0 Participants |
Primary
Objective Response Rate (ORR) (Phase II)
Evaluated per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT. Complete Response (CR) is a complete elimination of the tumor; Partial Response (PR) is 30% reduction. If a subject experienced a PR, this was required to be confirmed with a second scan at the next appropriate cycle.
Time frame: Up to 2 years
Population: Only Phase 2 subjects were evaluated for this outcome as Phase 1 subjects were only included in the protocol for safety evaluation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 Cohort 1 | Objective Response Rate (ORR) (Phase II) | 13 percent of participants |
Comparison: The primary objective of the phase II design compared ORR with historical rates (Judson et al. Lancet Onc., 2014). A 2-stage design with null hypothesis of 15% using a 1-sided 0.05 α level test has 85% power to detect an increase to 35%. This required up to 35 patients. After 2 responses in stage 1 (20 pts), the study moved to stage 2 (15 pts). If 10 responses were seen (29%), this would have ruled out an ORR of 15%. The study was closed when it became clear we would not meet this benchmark.
Secondary
Duration of Response
Duration of response is the mean time to progression for all subjects who responded.
Time frame: Up to 2 years
Population: Only 5 appropriate subjects had partial responses for evaluation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 Cohort 1 | Duration of Response | 247 Days | Standard Deviation 180 |
Secondary
Median Progression-free Survival (PFS)
The Kaplan-Meier method will be used to estimate median PFS.
Time frame: Up to 2 years
Population: This combined the phase I and phase II populations as we had intended for this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Cohort 1 | Median Progression-free Survival (PFS) | 8.1 months |
Secondary
Overall Survival (OS)
The Kaplan-Meier method will be used to estimate median OS.
Time frame: Up to 2 years
Population: This combined the phase I and phase II populations as we had intended for this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Cohort 1 | Overall Survival (OS) | 27.6 months |
Secondary
Time to Response
Average time to response
Time frame: Up to 2 years
Population: Only 5 appropriate subjects had partial responses for evaluation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 Cohort 1 | Time to Response | 152.2 Days | Standard Deviation 65 |