Retifanlimab (Anti-PD-1 Antibody) With Gemcitabine and Docetaxel in Patients With Advanced Soft Tissue Sarcoma

Memorial Sloan Kettering Cancer Center (MSK)

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Soft Tissue Sarcoma Adult; Sarcoma; Soft Tissue Sarcoma; Sarcoma,Soft Tissue

Treatments: Drug: Retifanlimab; Drug: Gemcitabine; Drug: Docetaxel

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT04577014

20-316

Details and patient eligibility

About

This study is being done to find out whether the study drug Retifanlimab, a monoclonal antibody against the PD-1 protein, combined with gemcitabine and docetaxel, is a safe and effective treatment for your disease. Gemcitabine and docetaxel are chemotherapy drugs that are commonly used to treat soft tissue sarcoma. Retifanlimab is an experimental drug that boosts the immune system's ability to fight cancer cells. The study researchers think that Retifanlimab may help gemcitabine and docetaxel work better against soft tissue sarcoma that is either locally advanced or has spread beyond its original location (metastasized), and it cannot be removed with surgery (unresectable).

Enrollment: 98 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Diagnosis of metastatic or locally advanced and unresectable high-grade soft tissue sarcoma. Unresectable is defined as:

  1. primary tumor cannot be safely removed surgically, or
  2. primary tumor would benefit from systemic therapy prior to a surgical approach

• Be willing and able to provide written informed consent

• Must consent to mandatory tumor biopsy (if deemed safe and feasible) for research studies at screening, if archival tissue is not available, and at C1D15, C3D15.

• Age ≥ 18 years

• ECOG performance status ≤ 1

• Presence of measurable disease per RECIST v1.1

  • Target lesions must not be chosen from a previously irradiated field unless there has been radiographically and/or pathologically documented tumor progression in that lesion prior to enrollment.

• No prior systemic therapy (see exclusion criteria, below)

• Negative serum pregnancy test in women of childbearing potential

• Patients with chronic HBV (HBsAg-positive with undetectable or low HBV DNA and normal ALT, or HBsAg-negative with anti-HBc-positive serology) and HCV (completed curative antiviral treatment with HCV viral load below the limit of quantification) may be eligible

  • Patients with HBV should be treated with suppressive antiviral therapy prior to enrollment
  • Patients with HCV must have completed curative therapy and have negative HCV viral load

• Adequate organ function, as defined in Table 2:

Table 2: Laboratory Parameters Required for Study Inclusion

Hematological Absolute neutrophil count (ANC): ≥ 1,500 /mcL Platelets: ≥ 75,000 / mcL Hemoglobin: ≥ 9g/dL or ≥ 5.6 mmol/L

Renal Serum creatinine: ≤ 1.5 X upper limit of normal (ULN) OR Measured or calculated creatinine clearance: ≥ 60 mL/min for patient with creatinine levels > 1.5 X institutional ULN (GFR can also be used in place of creatinine orCrCl)

Hepatic Serum total bilirubin: ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 ULN except patients with Gilbert's disease (≤ 3x ULN) AST (SGOT) and ALT (SGPT): ≤ 2.5 X ULN OR ≤ 5 X ULN for patients with liver metastases

Exclusion criteria

• Received any systemic therapy in the advanced or metastatic setting

  • Adjuvant or neoadjuvant therapies received ≥ 1 year prior to enrollment are permitted

• Unstable or deteriorating cardiovascular disease within the previous 6 months, including:

  • Unstable angina or myocardial infarction
  • CVA/stroke
  • New York Heart Association [NYHA] Class III or IV congestive heart failure
  • Uncontrolled clinically significant arrhythmias

• Current use of immunosuppressive medication, EXCEPT for the following:

  • Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection)
  • Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent
  • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)

• Evidence of clinically significant immunosuppression such as the following:

  • Primary immunodeficiency state such as Severe Combined Immunodeficiency Disease
  • Concurrent opportunistic infection
  • Receiving systemic immunosuppressive therapy (> 2 weeks) including oral steroid doses > 10 mg/day of prednisone or equivalent within 2 months prior to enrollment

• History or evidence of symptomatic autoimmune disease in past 2 years prior to enrollment.

  • Replacement therapy (e.g., thyroxine for hypothyroidism, insulin for diabetes or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment for autoimmune disease

• Uncontrolled HIV infection, as defined by one or more of the following:

  • Patients with CD4+ T-cell (CD4+) counts < 350 cells/uL
  • Patients with a history of an opportunistic infection secondary to AIDS
  • Patients on anti-microbials with drug-drug interactions with the study drugs on this protocol, who cannot be switched to alternative anti-microbials
  • Patients on antiretroviral therapy < 4 weeks
  • Patients with HIV viral load > 400 copies/mL

• Active Hepatitis B or Hepatitis C

• Patients who have received a live vaccine within 30 days of the start date of the planned study therapy (with the exception of COVID-19 vaccines)

• History of active TB (Bacillus Tuberculosis)

• Radiation therapy within 2 weeks prior to study day 1

• If patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy

• Women who are pregnant or breast feeding

• Patients expecting to conceive or father children within the projected duration of the trial, starting with the visit through 180 days after the last dose of study treatment(s)

• Prior organ transplantation including allogenic stem-cell transplantation

• Active infection requiring systemic therapy

• Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v5.0 Grade ≥ 3)

• Patients with prior history of interstitial lung disease and clinically significant pulmonary compromise, including those who have a requirement for supplemental oxygen use to maintain adequate oxygenation

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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98 participants in 10 patient groups

Phase I: Safety Run-In / Dose Level 0

Experimental group

Description:

A safety run-in (dose level 0 in Table 1, below) will be performed and enroll 6 patients with advanced high-grade sarcoma who are treatment naïve. Cycle one will consist of gemcitabine plus docetaxel at the institution's standard dose and schedule: 900 mg/m2 of gemcitabine on days 1 and 8, and 75 mg/m2 of docetaxel on day 8. Intravenous Retifanlimab at a flat dose of 210 mg will be administered every 3 weeks starting on C2D1 for a total of two cycles (cycles 2 and 3). All visits are to be done +/-3 days of the scheduled timepoints.

Treatment:

Drug: Docetaxel

Drug: Gemcitabine

Drug: Retifanlimab

Phase I: Dose De-escalation Level 1

Experimental group

Description:

If ≤ 1 patient out of 6 at dose level 0 has a dose-limiting toxicity during this safety run-in, then the dose de-escalation portion of the protocol will commence. Dose Level 1: Retifanlimab (Day 1) - 375 mg (flat dose) Gemcitabine (Days 1 and 8) - 900 mg/m2 Docetaxel (Day 8) - 75 mg/m2 All visits are to be done +/-3 days of the scheduled timepoints.

Treatment:

Drug: Docetaxel

Drug: Gemcitabine

Drug: Retifanlimab

Phase I: Dose De-escalation Level -1

Experimental group

Description:

Dose Level -1: Retifanlimab (Day 1) - 375 mg (flat dose) Gemcitabine (Days 1 and 8) - 750 mg/m2 Docetaxel (Day 8) - 60 mg/m2 All visits are to be done +/-3 days of the scheduled timepoints.

Treatment:

Drug: Docetaxel

Drug: Gemcitabine

Drug: Retifanlimab

Phase I: Dose De-escalation Level -2

Experimental group

Description:

Dose Level -2: Retifanlimab (Day 1) - 375 mg (flat dose) Gemcitabine (Days 1 and 8) - 675 mg/m2 Docetaxel (Day 8) - 50 mg/m2 All visits are to be done +/-3 days of the scheduled timepoints.

Treatment:

Drug: Docetaxel

Drug: Gemcitabine

Drug: Retifanlimab

Undifferentiated Pleomorphic Sarcoma/Myxofibrosarcoma

Experimental group

Description:

(UPS/MFS) After the RP2D is determined, 5 histology-specific cohorts (10 patients each), including UPS/MFS, LPS, LMS, vascular sarcoma, and other STS, will open for enrollment. Patients will be treated with the RP2D of gemcitabine/docetaxel (when administered in combination with Retifanlimab) for cycle 1, with Retifanlimab added on cycle 2 day 1 at a flat dose of 375 mg. Gemcitabine/docetaxel will continue for 5 additional cycles (total of 6 cycles), after which treatment with Retifanlimab will continue until unacceptable toxicity, disease progression, or the completion of 35 cycles (105 weeks) of Retifanlimab treatment. All visits are to be done +/-3 days of the scheduled timepoints.

Treatment:

Drug: Docetaxel

Drug: Gemcitabine

Drug: Retifanlimab

Liposarcoma/LPS

Experimental group

Description:

After the RP2D is determined, 5 histology-specific cohorts (10 patients each), including UPS/MFS, LPS, LMS, vascular sarcoma, and other STS, will open for enrollment. Patients will be treated with the RP2D of gemcitabine/docetaxel (when administered in combination with Retifanlimab) for cycle 1, with Retifanlimab added on cycle 2 day 1 at a flat dose of 375 mg. Gemcitabine/docetaxel will continue for 5 additional cycles (total of 6 cycles), after which treatment with Retifanlimab will continue until unacceptable toxicity, disease progression, or the completion of 35 cycles (105 weeks) of Retifanlimab treatment. All visits are to be done +/-3 days of the scheduled timepoints.

Treatment:

Drug: Docetaxel

Drug: Gemcitabine

Drug: Retifanlimab

Leiomyosarcoma/LMS

Experimental group

Description:

After the RP2D is determined, 5 histology-specific cohorts (10 patients each), including UPS/MFS, LPS, LMS, vascular sarcoma, and other STS, will open for enrollment. Patients will be treated with the RP2D of gemcitabine/docetaxel (when administered in combination with Retifanlimab) for cycle 1, with Retifanlimab added on cycle 2 day 1 at a flat dose of 375 mg. Gemcitabine/docetaxel will continue for 5 additional cycles (total of 6 cycles), after which treatment with Retifanlimab will continue until unacceptable toxicity, disease progression, or the completion of 35 cycles (105 weeks) of Retifanlimab treatment. All visits are to be done +/-3 days of the scheduled timepoints.

Treatment:

Drug: Docetaxel

Drug: Gemcitabine

Drug: Retifanlimab

Vascular Sarcoma

Experimental group

Description:

After the RP2D is determined, 5 histology-specific cohorts (10 patients each), including UPS/MFS, LPS, LMS, vascular sarcoma, and other STS, will open for enrollment. Patients will be treated with the RP2D of gemcitabine/docetaxel (when administered in combination with Retifanlimab) for cycle 1, with Retifanlimab added on cycle 2 day 1 at a flat dose of 375 mg. Gemcitabine/docetaxel will continue for 5 additional cycles (total of 6 cycles), after which treatment with Retifanlimab will continue until unacceptable toxicity, disease progression, or the completion of 35 cycles (105 weeks) of Retifanlimab treatment. All visits are to be done +/-3 days of the scheduled timepoints.

Treatment:

Drug: Docetaxel

Drug: Gemcitabine

Drug: Retifanlimab

Other Soft tissue sarcoma/STS

Experimental group

Description:

After the RP2D is determined, 5 histology-specific cohorts (10 patients each), including UPS/MFS, LPS, LMS, vascular sarcoma, and other STS, will open for enrollment. Patients will be treated with the RP2D of gemcitabine/docetaxel (when administered in combination with Retifanlimab) for cycle 1, with Retifanlimab added on cycle 2 day 1 at a flat dose of 375 mg. Gemcitabine/docetaxel will continue for 5 additional cycles (total of 6 cycles), after which treatment with Retifanlimab will continue until unacceptable toxicity, disease progression, or the completion of 35 cycles (105 weeks) of Retifanlimab treatment. All visits are to be done +/-3 days of the scheduled timepoints.

Treatment:

Drug: Docetaxel

Drug: Gemcitabine

Drug: Retifanlimab

Advanced sarcoma who have progressed on prior treatment

Experimental group

Description:

Participants will have advanced sarcoma who have progressed on prior treatment and have an immune-enriched/non-fibrotic TME

Treatment:

Drug: Retifanlimab