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
participants 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 participants: 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 participants: 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,
participants may enroll with a pathologist's report showing a histologic diagnosis of
prostate cancer and a clinical course consistent with the disease.
Participants must have metastatic disease
- mCSPC participants must be within 134 days of starting ADT.
- mCRPC participants 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
participants, 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 participants will receive a maximum of 6
cycles. mCRPC participants 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 participants 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 participants will be enrolled onto the trial in the following expansion
cohorts, each of which will receive the determined safe dose of M9241.
- mCSPC participants: 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 participants: 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
participants.
- INCLUSION CRITERIA:
- Participants must have documented histopathological confirmation of prostate cancer.
If no pathologic specimen is available, participants may enroll with a pathologist's
report showing a histologic diagnosis of prostate cancer and a clinical course
consistent with the disease.
- Participants 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.
- mCSPC participants:
- Participants must be within 134 days of starting ADT.
- If participants are on ADT and responding, this may impact the findings on scans. Pre-
treatment scans could be used to confirm that participants 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 participants 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).
- mCRPC participants:
- Must have been previously treated with modern anti-androgens such as abiraterone,
enzalutamide, apalutamide, or darolutamide.
- 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.
- 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 participants <18 years
of age, children are excluded from this study.
- ECOG performance status 0-2.
- Participants must have adequate organ and marrow function as defined below:
- Absolute neutrophil count >=1,500/mcL, without CSF support
- Platelets >=100,000/mcL
- Hemoglobin >9 g/dL
- PT <= 1.5 x ULN
- aPIT 1.5 x ULN
- Total bilirubin <= upper limit of normal (ULN), OR in participants with Gilbert s
syndrome, a total bilirubin <= 3.0
- Serum albumin >=2.8 g/dL
- AST(SGOT)/ALT(SGPT) <=1.5 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 participants with
serum creatinine levels > 1.5 ULN
- 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.
- 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.
- Participants with prior immune checkpoint therapy are eligible to enroll upon PI
discretion.
EXCLUSION CRITERIA:
- 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. Participants 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 participants or limit treatment efficacy
- 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
- Serious intercurrent medical illness that, in the judgment of the investigator, would
interfere with participant s ability to carry out the treatment program.
- Participants with radiation proctitis and bleeding episodes within 6 months of
enrollment are excluded.
- 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).
- Receipt of any investigational agent within 28 days (or 60 days for an antibody-based
therapy) before the first planned dose of study drugs.
- Participants who are positive for Hepatitis B surface antigen and/or Anti-Hepatitis C
antibody
- Uncontrolled hypertension (SBP>170/ DBP>105)
- Participants unwilling to accept blood products as medically indicated.
- Has received or will receive a live vaccine within 30 days prior to the first
administration of study intervention. Seasonal flu vaccines that do not contain a live
virus are permitted. Locally approved COVID vaccines are permitted.
- Participants who have had prior docetaxel for mCRPC
- Participants who have had progression within 3 months of completing docetaxel for
mCSPC
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to M7824 and/or M9241 investigational agents used in the study
- 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).
- The subject has active brain metastases or epidural disease.
- Participants with greater than or equal to grade 2 peripheral neuropathy (defined by
CTCAE 5.0) at baseline.
