Clinical Trials /

Bintrafusp Alfa (M7824) and M9241 in Combination With Docetaxel in Adults With Metastatic Castration Sensitive and Castration Resistant Prostate Cancer

NCT04633252

Description:

Background: Metastatic castration sensitive and castration resistant prostate cancer (mCSPC and mCRPC) are prostate cancers that have spread to other parts of the body. Use of the drug docetaxel with androgen deprivation therapy can improve survival for men with mCSPC. Researchers want to see if combining this treatment with other drugs can help delay the time it takes for mCSPC and mCRPC to get worse. Objective: To learn if giving docetaxel with M7824 and M9241 is safe and effective for men with prostate cancer. Eligibility: Men age 18 and older with mCSPC or mCRPC. Design: Participants will be screened with a medical history and physical exam. Their diagnosis will be confirmed. Their symptoms and how well they do their normal activities will be reviewed. They will have blood and urine tests. Their heart will be evaluated. They will have imaging scans of the chest, abdomen, and pelvis. They will have bone scans with intravenous (IV) injections of Tc99 to check for tumor spread in the bones. Some screening tests will be repeated during the study. Participants may have tumor biopsies. Participants will get treatment in cycles. Each cycle will last 21 days. They will get docetaxel and M7824 through IV infusion. They will get M9241 as an injection under the skin. Participants with mCSPC will have up to 6 cycles. Those with mCRPC will be treated until they cannot tolerate the side effects or their disease gets worse. Participants will have a follow-up visit 30 days after treatment ends. Those with mCSPC will then have follow-up visits at the clinic every 3 months....

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Bintrafusp Alfa (M7824) and M9241 in Combination With Docetaxel in Adults With Metastatic Castration Sensitive and Castration Resistant Prostate Cancer
  • Official Title: A Phase I/II Study of Bintrafusp Alfa (M7824) and M9241 in Combination With Docetaxel in Adults With Metastatic Castration Sensitive and Castration Resistant Prostate Cancer

Clinical Trial IDs

  • ORG STUDY ID: 210001
  • SECONDARY ID: 21-C-0001
  • NCT ID: NCT04633252

Conditions

  • Cancer Of Prostate
  • Prostate Neoplasms

Interventions

DrugSynonymsArms
ADT1/Dose Escalation
Prednisone1/Dose Escalation
M78242/Safety Run-in
Docetaxel1/Dose Escalation
M92411/Dose Escalation

Purpose

Background: Metastatic castration sensitive and castration resistant prostate cancer (mCSPC and mCRPC) are prostate cancers that have spread to other parts of the body. Use of the drug docetaxel with androgen deprivation therapy can improve survival for men with mCSPC. Researchers want to see if combining this treatment with other drugs can help delay the time it takes for mCSPC and mCRPC to get worse. Objective: To learn if giving docetaxel with M7824 and M9241 is safe and effective for men with prostate cancer. Eligibility: Men age 18 and older with mCSPC or mCRPC. Design: Participants will be screened with a medical history and physical exam. Their diagnosis will be confirmed. Their symptoms and how well they do their normal activities will be reviewed. They will have blood and urine tests. Their heart will be evaluated. They will have imaging scans of the chest, abdomen, and pelvis. They will have bone scans with intravenous (IV) injections of Tc99 to check for tumor spread in the bones. Some screening tests will be repeated during the study. Participants may have tumor biopsies. Participants will get treatment in cycles. Each cycle will last 21 days. They will get docetaxel and M7824 through IV infusion. They will get M9241 as an injection under the skin. Participants with mCSPC will have up to 6 cycles. Those with mCRPC will be treated until they cannot tolerate the side effects or their disease gets worse. Participants will have a follow-up visit 30 days after treatment ends. Those with mCSPC will then have follow-up visits at the clinic every 3 months....

Detailed Description

      Background:

      A phase III trial demonstrated that combining docetaxel and androgen deprivation therapy
      (ADT) significantly improved survival (57.6 vs 44.0 months (hazard ratio HR=0.56,
      (0.44-0.70), p <0.0001) for men with metastatic castration sensitive prostate cancer (mCSPC).
      The greatest benefit was seen in men with "high volume disease" (visceral disease or 4+ bone
      lesions with at least one beyond the pelvis and spine.)

      Clinical data has indicated that PSA <0.20 ng/mL seven months after starting androgen
      deprivation therapy (ADT) is prognostic for overall survival based on data from the phase III
      trial.

      Docetaxel has limited efficacy in metastatic castration resistant prostate cancer (mCRPC)
      patients who have already progressed on anti-androgen therapy (abiraterone or enzalutamide).

      Anti-PD-L1/TGF-beta trap (M7824) is a novel first-in-class bifunctional fusion protein
      composed of a monoclonal antibody against PD-L1 fused to the extracellular domain of human
      TGF-beta receptor II (TGFbetaRII), which effectively functions to sequester or "trap" all
      three TGF-beta isoforms. A phase I study of M7824 (NCT02517398) demonstrated a manageable
      safety profile and clinical efficacy among patients with heavily pre-treated advanced solid
      tumors.

      M9241 is an immunocytokine that can enhance the efficacy of anti-PDL1 targeting antibodies
      such as M7824.

      Preclinical data suggests that there may be synergistic anti-tumor effects, when docetaxel,
      M9241 and M7824 are combined.

      Objectives:

      Phase I:

      To evaluate safety and tolerability of docetaxel in combination with M7824 and M9241 in
      patients who have metastatic prostate cancer.

      Phase II:

      Determine clinical efficacy in adults with prostate cancer treated with docetaxel in
      combination with Anti-PD-L1/TGF-beta trap (M7824) and the immunocytokine, M9241.

      For mCSPC patients: Clinical efficacy will be measured by prostate specific antigen (PSA <0.2
      ng/ml) seven months after start of androgen deprivation therapy (ADT).

      For mCRPC patients: Clinical efficacy will be measured by an increase in their median
      progression free survival (PFS).

      Eligibility:

      Men age >=18 years

      Histopathological confirmation of prostate cancer. If no pathologic specimen is available,
      patients may enroll with a pathologist's report showing a histologic diagnosis of prostate
      cancer and a clinical course consistent with the disease.

      Patients must have metastatic disease

        -  mCSPC patients must be within 134 days of starting ADT.

        -  mCRPC patients must have been previously treated with ADT.

      Design:

      Open-label, single-center, non-randomized Phase I/II study

      To ensure safety of the combination before using in larger numbers of mCSPC and mCRPC
      patients, M9241 will be escalated from a starting dose of 12 mcg/kg and a second dose level
      of 16.8 mcg/kg along with docetaxel. mCSPC patients will receive a maximum of 6 cycles. mCRPC
      patients will continue until progression or unacceptable toxicity.

      Once the recommended phase II dose (RP2D) of M9241 has been defined, we will do a safety
      run-in cohort to include another 6 patients to determine the safety of the combination of
      docetaxel 75 mg/m^2 (given every 3 weeks x 6 cycles starting at Cycle 1), with M9241 at the
      RP2D and M7824 (2400 mg), given every 3 weeks from cycle 2 through cycle 6).

      The remaining patients will be enrolled onto the trial in the following expansion cohorts,
      each of which will receive the determined safe dose of M9241.

        -  mCSPC patients: ADT followed by simultaneous docetaxel 75 mg/m^2 (given every 3 weeks x
           6 cycles starting at Cycle 1), with M9241 at the RP2D and M7824 (2400 mg), given every 3
           weeks from cycle 2 through cycle 6). Prednisone is optional and may be given orally at 5
           mg once a day. Androgen Deprivation Therapy (ADT) may include GnRH agonist or monthly
           degarelix converted to GnRH agonist after 3 months

        -  mCRPC patients: docetaxel 75 mg/m^2 (given every 3 weeks starting at Cycle 1) with M9241
           at the RP2D and M7824 (2400 mg), given every 3 weeks from cycle 2 onwards until disease
           progression or unacceptable toxicity. Prednisone will be given 5 mg twice a day for each
           dose or 10 mg once a day. ADT will be continued as per standard of care. Testosterone
           suppression will be maintained throughout the study

      It is anticipated that approximately 1.5 to 2 years may be required for accrual of up to 86
      patients.
    

Trial Arms

NameTypeDescriptionInterventions
1/Dose EscalationExperimentalDocetaxel plus M9241 dose escalation with optional prednisone and ADT as part of SOC
  • ADT
  • Prednisone
  • Docetaxel
  • M9241
2/Safety Run-inExperimentalDocetaxel plus M9241 RP2D plus M7824 with optional prednisone and ADT as part of SOC
  • ADT
  • Prednisone
  • M7824
  • Docetaxel
  • M9241
3/mCSPC: Dose ExpansionExperimentalDocetaxel plus M9241 RP2D plus M7824 with optional prednisone and ADT as part of SOC
  • ADT
  • Prednisone
  • M7824
  • Docetaxel
  • M9241
4/mCRPC: Dose ExpansionExperimentalDocetaxel plus M9241 RP2D plus M7824 with optional prednisone and ADT as part of SOC
  • ADT
  • Prednisone
  • M7824
  • Docetaxel
  • M9241

Eligibility Criteria

        -INCLUSION CRITERIA:

          1. Patients must have documented histopathological confirmation of prostate cancer. If no
             pathologic specimen is available, patients may enroll with a pathologist's report
             showing a histologic diagnosis of prostate cancer and a clinical course consistent
             with the disease.

          2. Patients must have metastatic disease, defined as at least one lesion on TC99 bone
             scan or at least one lesion that is measurable per, per RECIST 1.1.

          3. mCSPC patients:

               -  Patients must be within 134 days of starting ADT.

               -  If patients are on ADT and responding, this may impact the findings on scans.
                  Pre- treatment scans could be used to confirm that patients have metastatic
                  high-volume disease in such cases.

                    -  For Cohorts 1 and 2, Dose escalation and Safety Run-in, only: mCSPC may have
                       high or low volume disease.

                    -  For Cohort 3, Dose Expansion: mCSPC patients must have high volume disease
                       (as defined by visceral lesion or 4 or greater bone lesions, at least one of
                       which is beyond the spine and pelvis).

          4. mCRPC patients:

               -  Must have been previously treated with abiraterone or enzalutamide.

               -  Must have not had progression while on docetaxel if given for mCSPC or within 3
                  months of completing docetaxel for mCSPC.

               -  Progression defined as either rising PSA greater than 2.0 ng/ml or radiographic
                  evidence of progression seen on CT scan or TC-99 bone scan.

               -  Toxicities related to prior therapy, including surgery and/ or radiation, must
                  have resolved to <= grade 1.

          5. Men age >=18 years. Because no dosing or adverse event data are currently available on
             the use of M7824 and/or M9241in combination with docetaxel in patients <18 years of
             age, children are excluded from this study.

          6. ECOG performance status 0-2.

          7. Patients must have adequate organ and marrow function as defined below:

               -  Absolute neutrophil count >=1,500/mcL, without CSF support

               -  Platelets >=100,000/mcL

               -  Total bilirubin <= 1.5 x upper limit of normal (ULN), OR in patients with Gilbert
                  s syndrome, a total bilirubin <= 3.0

               -  Serum albumin >=2.8 g/dL

               -  AST(SGOT)/ALT(SGPT) <=2.5 X institutional upper limit of normal

               -  Serum Creatinine OR Creatinine Clearance <= 1.5 X institutional upper limits of
                  normal OR >=50 mL/min/1.73 m^2 calculated by eGFR in the clinical lab for
                  patients with serum creatinine levels > 1.5 ULN

          8. The effects of M7824 and/or M9241 in combination with docetaxel on the developing
             human fetus are unknown. For this reason and because docetaxel agents as well as other
             immuno-therapeutic agents used in this trial are known to be teratogenic, sexually
             active subjects and their female partners must agree to use medically accepted barrier
             methods of contraception (e.g., male or female condom)after enrollment on study ,
             during the study treatment and for 3 months after the last dose of docetaxel or M7824
             or M921, even if oral contraceptives are also used. Should a woman become pregnant or
             suspect she is pregnant while her partner is participating in this study, she should
             inform her treating physician immediately and her partner should inform the study
             doctor immediately.

          9. Ability of subject to understand and the willingness to sign a written informed
             consent document. Subject should be willing to travel to the NIH for follow-up visits.

         10. Patients with prior immune checkpoint therapy are eligible to enroll upon PI
             discretion.

        EXCLUSION CRITERIA:

          1. Immunocompromised status due to:

               -  Human immunodeficiency virus (HIV) positivity

               -  Active autoimmune diseases such as Addison's disease, Hashimoto's thyroiditis,
                  systemic lupus erythematosus, Sjogren syndrome, scleroderma, myasthenia gravis,
                  Goodpasture syndrome or active Grave's disease. Patients with a history of
                  autoimmunity that has not required systemic immunosuppressive therapy or does not
                  threaten vital organ function including CNS, heart, lungs, kidneys, skin, and GI
                  tract will be allowed.

               -  Other immunodeficiency diseases that in the opinion of the investigator could
                  compromise the patient or limit treatment efficacy

          2. Chronic administration (defined as daily or every other day for continued use > 14
             days) of corticosteroids (>10 mg daily prednisone equivalent) deemed systemic by
             investigator within 28 days before the first treatment on-study treatment. Use of
             inhaled steroids, nasal sprays, and topical creams (for small body areas) including
             adrenal replacement steroid doses up to 10 mg daily prednisone equivalents are
             permitted in the absence of active autoimmune disease

          3. Serious intercurrent medical illness that, in the judgment of the investigator, would
             interfere with patient s ability to carry out the treatment program.

          4. Patients with radiation proctitis and bleeding episodes within 6 months of enrollment
             are excluded.

          5. Current use of other medications for urinary symptoms including 5-alpha reductase
             inhibitors (finasteride and dutasteride) and alternative medications known to alter
             PSA (e.g. phytoestrogens and saw palmetto).

          6. History of atopic dermatitis or active skin condition (acute, chronic, exfoliative)
             that disrupts the epidermis

          7. Receipt of any investigational agent within 28 days (or 60 days for an antibody-based
             therapy) before the first planned dose of study drugs.

          8. Patients who are positive for Hepatitis B surface antigen and/or Anti-Hepatitis C
             antibody

          9. Uncontrolled hypertension (SBP>170/ DBP>105)

         10. Patients who have had prior docetaxel for mCRPC

         11. Patients who have had progression within 3 months of completing docetaxel for mCSPC

         12. History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to M7824 and/or M9241 investigational agents used in the study

         13. The subject has had evidence within 2 years of the start of study treatment of another
             active malignancy which required systemic treatment (except for nonmelanoma skin
             cancers or carcinoma in situ of the bladder).

         14. The subject has active brain metastases or epidural disease.

         15. Patients with greater than or equal to grade 2 peripheral neuropathy (defined by CTCAE
             5.0) at baseline.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:To evaluate safety and tolerability of docetaxel in combination with M7824 and M9241 in patients who have metastatic prostate cancer.
Time Frame:DLT observation period (until the end of 6 weeks)
Safety Issue:
Description:of the number and type of toxicities noted for patients who are evaluable for toxicity

Secondary Outcome Measures

Measure:Evaluate radiographic response rates
Time Frame:4-8 weeks
Safety Issue:
Description:Tumor progression on scans
Measure:Evaluate percentage of patients with a 50% PSA decline from baseline
Time Frame:4-8 weeks
Safety Issue:
Description:PSA levels
Measure:Evaluate radiographic and biochemical time to progression for mCSPC patients
Time Frame:7 months
Safety Issue:
Description:PSA levels and tumor progression on scans

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Chemoimmunotherapy
  • Anti PD-L1 TGF Beta-Trap
  • NHS IL-12
  • Check point inhibitor
  • Combination Therapy

Last Updated

November 20, 2020