Phase III Trial of Docetaxel vs. Docetaxel and Radium-223 for Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Prostate cancer is the second leading cause of cancer deaths in men. The
terminal phase of the disease is termed metastatic castration resistant
prostate cancer (mCRPC), in which the disease progresses despite testosterone
lowering agents. Ultimately, the prostate cancer can develop a host of
resistance mechanisms to castrating therapy, including androgen receptor (AR)
overexpression and mutation, and intratumoral androgen biosynthesis. There are
currently six active therapies for the treatment of mCRPC. As a standard, most
patients will either progress through abiraterone or enzalutamide. After first
line therapy for mCRPC, patients will largely be resistant to further AR
directed therapy. Chemotherapy at this point, using docetaxel, has a
well-established role in this clinical context, even after abiraterone and
enzalutamide resistance. The other treatment options are radium-223,
Sipuleucel-T and cabazitaxel. However, the magnitude of the overall survival
(OS) benefit is modest for mCRPC. Castration-resistant prostate cancer patients
with bone metastases would benefit from new and additional treatment options to
improve survival, to delay disease progression, and to relieve pain, preferably
with a more favorable safety profile than existing treatments.
Prostate cancer is the paradigm of a bone-tropic solid tumor, a characteristic
that both renders it clinically devastating, yet uniquely susceptible to
treatments that target bone formation and osteoblastic activity. It is the same
process of abnormal bone metabolism that places the subject at risk of the
significant morbidities of metastatic prostate cancer and death and death that
can be leveraged to deliver treatments to a single organ system and impact the
majority of the disease burden. Radium-223 is a hydroxyappetite-targeted
therapy that is incorporated into calcium phosphate by substituting for
calcium. It selectively accumulates in areas of increased bone turnover that
surround cancer metastases, where it emits high-energy, short-range (<100 µm)
alpha particles with minimal radiation effects on bone marrow.34,11 In
preclinical models, it can reduce abnormal bone production, reduce tumor
burden, and reduce dysregulated bone deposition. Clinically, it prolongs life
and reduces the risk of symptomatic skeletal events in men with metastatic
castration resistant disease, when given at a dose of 55 kBq/kg every four
weeks, for six doses.
Docetaxel is an antimitotic chemotherapeutic agent that interferes with
microtubule dynamics, resulting in the inhibition of cell division,
intracellular organelle trafficking, and, perhaps, androgen receptor
translocation.37 Docetaxel given at a dose of 75 mg/m2 administered every three
weeks in combination with prednisone was the first drug to be shown to prolong
life in men with mCRPC.
The hypothesis of targeting both the host organ of metastatic disease with a
bone-seeking radiopharmaceutical (BSR) and targeting the tumor itself with
chemotherapy is predicated not only on the concept of multicompartment
targeting. These two agents may well also cross-sensitize, as chemotherapy may
enhance the effects of the radioactive energy emitted by radium-223, and radium
may enhance the cytotoxic effects of chemotherapy. Furthermore, earlier studies
that did not utilize taxane-based chemotherapy or alpha emitting BSRs showed
earlier promise of potential clinical benefit. Such older studies, however, did
not employ agents known to prolong life, and risked higher marrow toxicity than
either agent used alone.
This trial advanced this concept by combining life-prolonging taxane-based
chemotherapy with life-prolonging alpha emitting therapy. This regimen not only
offers the promise of combining two active agents, but minimizing toxicity
because of the relatively low marrow toxicity of radium due to the short tissue
penetration of alpha particles. We therefore conducted a phase Ib/IIa study to
determine dose, safety, feasibility, and early treatment effects of the
combination of docetaxel and radium-223.

This study has been transitioned to CTIS with ID 2024-513867-19-00 check the CTIS register for the current data.

Primary objective:
Compare overall survival for subjects treated with docetaxel versus
subjects treated with docetaxel plus raduim-223
Secondairy objectives:
To compare:
a. Radiographic progression free survival as defined in PCWG3 criteria;
b. Symptomatic Skeletal event free survival;
c. Time to total alkaline phosphatase (ALP) progression;
d. On-treatment alterations in quality of life as assessed by FACT-P, BPI, and
BFI measures between subjects who receive docetaxel with those who receive
docetaxel and radium-223.

To determine if there is excessive:
e. Febrile neutropenia in subjects treated with docetaxel plus radium-223;
f. Treatment discontinuation in subjects who are on their fourth line of
therapy.

This is a controlled, randomized, open, parallel group, Multicenter, Phase III
Trial of Docetaxel vs. Docetaxel and Radium-223 for Metastatic
Castration-Resistant Prostate Cancer (mCRPC). Patients with histological or
cytological proof of Metastatic Castration-Resistant Prostate Cancer (mCRPC)
will be randomized 1:1 in arm A or arm B.

Treatment Plan

Arm A: Docetaxel 75 mg/m2 will be administered IV every three weeks for 10
doses. Prednisone will be given at a dose of 5mg orally twice daily.
Dexamethasone will be given per institutional practice. Growth factor support
may be used per ASCO guidelines, but use as primary prophylaxis should be
avoided.

Arm B: Docetaxel 60 mg/m2 will be administered IV every 3 weeks for 10 doses.
Prednisone, dexamethasone, growth factor support will be used per above.
Radium-223 will be administered at 55 kBq/kg, 6 injections at 6 weeks
intervals.

Arm A: Docetaxel 75 mg/m2 will be administered IV every three weeks for 10
doses. Prednisone will be given at a dose of 5mg orally twice daily.
Dexamethasone will be given per institutional practice. Growth factor support
may be used per ASCO guidelines, but use as primary prophylaxis should be
avoided.

Arm B: Docetaxel 60 mg/m2 will be administered IV every 3 weeks for 10 doses.
Prednisone, dexamethasone, growth factor support will be used per above.
Radium-223 will be administered at 55 kBq/kg, 6 injections at 6 weeks
intervals.

The drugs used in this study may affect how different parts of your body work
such as your liver, kidneys, heart, and blood. The study doctor will be testing
your blood and will let you know if changes occur that may affect your health.

Listed below are the most common and the most serious side effects that
researchers know about. There might be other side effects that researchers do
not yet know about. If important new side effects are found, the study doctor
will discuss these with you.
Possible Side Effects of Docetaxel (chemotherapy) for the Treatment of Prostate
Cancer

Common, some may be serious (in 100 people receiving docetaxel, more than 20
and up to 100 may have):
• Low red blood cell count (anemia)
• Low white blood cells (neutropenia)
• Infection
• Fluid retention
• Pain or numbness in hands and feet (peripheral neuropathy)
• Loss of hair (alopecia)
• Nail Changes
• Nausea
• Diarrhea
• Inflamed and sore mouth (stomatitis)
• Fatigue

Occasional, some may be serious (in 100 people receiving docetaxel, from 4 to
20 may have):
• Bleeding from the nose
• Allergic reactions
• Weakness in your hands and arms (neuropathy motor)
• Rash
• Changes in taste
• Vomiting
• Loss of appetite
• Cough
• Difficult breathing (dyspnea)
• Worsening cardiac function. Damage may make you feel weak, have difficulty
breathing, or gain weight from fluid retention.
• Muscle pain (myalgia)
• Tearing
• Joint pain (arthralgia)

Rare, and serious (in 100 people receiving docetaxel, 3 or fewer may have):
• Low platelets (thrombocytopenia), which may increase your risk of bleeding
• Fever associated with low levels of a type of white blood cell (neutrophils)
• Inflammation of the lung (pneumonitis), which can manifest as shortness of
breath
In addition to side effects outlined above for Group A and Group B, people in
this study who are in Group B may also experience the possible side effects of
Radium-223 listed below.

Possible Side Effects of Radium-223

Common, some may be serious (in 100 people receiving radium-223, more than 20
and up to 100 may have):
• Nausea
• Vomiting
• Diarrhea
• Swelling in the feet, ankles, and legs (peripheral edema)
• Lowering of the blood counts. This side effect may manifest as:
o Low red cells (anemia)- low red cells can cause tiredness, low energy, and
decreased ability to exercise, among other symptoms. Some people may require
blood transfusions.
o Low white cells- these cells fight infection. If the levels go very low, you
may be susceptible to infection.
o Low platelets (thrombocytopenia), low platelets can cause bruising or
bleeding. Some patients may require platelet transfusions.
• Fatigue
• Dizziness
• Shortness of breath
• Bone pain

Occasional, some may be serious (in 100 people receiving radium-223, from 4 to
20 may have:
• Bone marrow failure (pancytopenia) - lowering of blood cell counts, which may
cause you to have shortness of breath, increase your heart rate, or cause you
to feel weak. Rarely, this condition may be permanent
• Injection-site reactions (e.g. redness of the skin, pain and swelling)

An increased risk of developing cancerous bone tumors has been reported
following exposure to different forms of radiation (including radioisotopes).
However, only one case has been reported in clinical studies with radium-223.

The effect of radium-223 on the patient*s fertility is unknown.

As with any radiotherapy treatment, there is also a risk of late side effects
occurring months or years after the treatment. It is important to let your
study doctor know of any changes to your health while you are receiving
treatment or after you have completed this research study.
For more information about risks and side effects, ask your study doctor.

Possible Side Effects From Prednisone
• Confusion, excitement, restlessness
• Headache
• Nausea and vomiting
• Trouble sleeping
• Weight gain

Call the study doctor right away if you have an allergic reaction like skin
rash, itching or hives, swelling of face, lips or tongue.

Bone Scan Risks
Risk to bone scans is near negligible with minimal radiation.

CT Risks
A CT Scan exposes you to radiation. No amount of radiation is safe, and
exposure adds up over a lifetime. The total dose of radiation from a CT scan
is about three times the amount of radiation you would normally be exposed to
in one year ("background radiation"). The amount of radiation can vary
depending on the part of the body that is being examined. If you have more
procedures that expose you to radiation, your risk will go up. Risks of harm
include getting a cancer, or changes to your genes. Your risk of harm may be
as high as 1 in 1,000. Your study doctor can discuss this with you in more
detail.

MRI Risks
The MRI may mean some added discomfort for you. In particular, you may be
bothered by feelings of claustrophobia and by the loud banging noise during the
MRI. Temporary hearing loss has been reported from this loud noise. You may
be asked to wear ear protection. At some time during the test, you may be
asked to hold your breath for a while, which can be uncomfortable.

EMF Risks
The effects of electromagnetic fields (EMF) on the human body are not well
understood. There is a very small possibility that this exposure from the MRI
could have a bad effect such as causing some form of cancer. The exposure in
this study is not expected to greatly increase EMF risks, but the exact
increase is unknown.

New Information
You will be told about any new information that might change your decision to
be in this study. You may be asked to sign a new consent form if this occurs.

Risks and side effects of tests/procedures:
Drawing blood may be painful or cause some bruising. We will take a maximum of
70 ml of blood from you per visit. This amount does not cause any problems in
adults. To compare: a blood donation involves 500 ml of blood being taken each
time.

Bone scan, X-Ray or CT and/or MRI of the chest, abdomen, and pelvis. These
tests involves using radiation. The total amount of radiation you will be
exposed to in this study is [XX] mSv. To compare: the background radiation in
the Netherlands is ~2.5 mSv per year.

If you participate in scientific research involving exposure to radiation
frequenty?, you should discuss with the investigator whether participation at
this moment would be safe.
The radiation used during the study may lead to damage to your health. However,
this risk is small. We nevertheless advise you not to participate in another
scientific study involving exposure to radiation in the near future.
Examinations or procedures involving radiation for medical reasons are not a
problem.