A Dynamic Allocation Modular Sequential Trial of Approved and Promising Therapies in Men With Metastatic Castrate Resistant Prostate Cancer (DynaMO)

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to Group 1
and receive apalutamide, abiraterone, and prednisone. After 8 weeks of receiving treatment in
Group 1, you will then have blood (about 4 teaspoons) drawn for biomarker testing. The result
of this biomarker test will determine whether you will continue the study in Group 2 or Group
3.

If you are found to be eligible for Group 2, you will be randomly assigned (as in the flip of
a coin) to 1 of 2 study groups. This is done because no one knows if one study group is
better, the same, or worse than the other group. You will have an equal chance (50/50) of
being assigned to either group:

- If you are assigned to Group 2A, you will continue to receive apalutamide, abiraterone,
and prednisone alone.

- If you are assigned to Group 2B, you will receive apalutamide, abiraterone, prednisone,
and ipilimumab.

If you are found to be eligible for Group 3, you will receive apalutamide, abiraterone, and
prednisone, plus cabazitaxel and carboplatin.

After treatment in Groups 2 and 3 is complete, you will be assigned to Group 4 and you will
go back to only taking apalutamide, abiraterone, and prednisone.

Study Drug Administration:

Each study cycle is 21 days.

- You will take 4 tablets of abiraterone acetate and 4 tablets of apalutamide by mouth
every day while you are on study. The tablets should be taken at the same time every
day. °You will take all of these drugs throughout the entire study.

- You should not eat or drink anything except water from 2 hours before your dose until 1
hour after your dose.

- You will also take 1 tablet of prednisone by mouth 2 times every day while you are on
study. Prednisone should be taken with food.

The study drug bottle will also include a small packet (called a desiccant) that is placed in
the bottle to protect the study drug. Do not eat or remove the desiccant. You should store
your study drug in the study bottle and not place your pills in a separate container, such as
a pill container.

If you are assigned to Group 2B, you will also receive ipilimumab by vein over 90 minutes on
Day 1 of Cycles 4, 5, 6, and 7.

If you are assigned to Group 3, you will receive cabazitaxel and carboplatin by vein on Day 1
of Cycles 4, 5, 6, and 7. You will receive cabazitaxel by vein over 60 minutes and then
receive carboplatin, also by vein, over 60 minutes.

After Cycle 7, if you are assigned to Group 4, you will return to taking 4 tablets of
abiraterone acetate and 4 tablets of apalutamide and prednisone by mouth every day, just like
in Group 1.

Study Visits:

On Day 1 of Cycles 2, 3, 4, 5, 6, 7, 8, 9, and 10, then every 2 cycles after that for one
year, then every 4 cycles after that:

- You will have a physical exam.

- Blood (about 3 teaspoons) will be drawn for routine tests, for tests of your liver
function, and to measure your PSA levels.

Every 2 weeks for the first 9 weeks (Cycles 1-3) and every week of Cycles 4-7, blood (about
3-4 teaspoons) will be drawn for routine tests and to check your thyroid (Cycle 1 only).

At Week 3 of Cycle 3:

- You will have a physical exam.

- Blood (about 3 teaspoons) will be drawn for routine tests, for tests of your liver
function, and to measure your PSA levels.

- You will have a bone scan and either a CT scan or MRI of your abdomen and pelvis. If the
doctor thinks it is needed, you will also have a chest CT scan.

- Blood (about 3 teaspoons) and urine will be collected for biomarker testing.

- A bone marrow biopsy and aspiration will be collected for biomarker testing.

If you are in Group 2B, on Day 1 of Cycles 4, 5, 6, 7 and 8, blood (about 1 teaspoon) will be
drawn to test your thyroid and adrenal function.

If you are in Group 2A, on Day 1 of Cycle 8:

- Blood (about 3 teaspoons) will be drawn for biomarker testing.

- A bone marrow biopsy and aspiration will be collected for biomarker testing.

If you are in Group 2B, about 3 weeks after your last dose of ipilimumab:

- Blood (about 3 teaspoons) will be drawn for biomarker testing

- A bone marrow biopsy and aspiration will be collected for biomarker testing.

If you are in Group 3, about 3 weeks after your last dose of cabazitaxel and carboplatin:

- Blood (about 3 teaspoons) will be drawn for biomarker testing.

- A bone marrow biopsy and aspiration will be collected for biomarker testing.

If you are in Group 2A or 2B, at Weeks 21, 33, 45, and every 16 weeks after that:

- You will have a bone scan, and either a CT scan or MRI of your abdomen and pelvis. If
the doctor thinks it is needed, you will also have a chest CT scan.

- Blood (about 3 teaspoons) and urine will be collected for biomarker testing.

If you are in Group 3, at Weeks 15, 21, 33, 45, 57, and every 16 weeks after that:

- You will have a bone scan, and either a CT scan or MRI of your abdomen and pelvis. If
the doctor thinks it is needed, you will also have a chest CT scan.

- Blood (about 3 teaspoons) and urine will be collected for biomarker testing.

If the study doctor thinks it is needed, you may have additional bone scans or CT scans or
MRIs of the abdomen, pelvis, or chest to check the status of the disease.

Length of Treatment:

You may continue taking the study drugs for as long as the doctor thinks it is in your best
interest. You may no longer be able to take the study drugs if the disease gets worse, if
intolerable side effects occur, or if you are unable to follow study directions.

If the study drug becomes commercially available while you are on study, you may begin to
receive it off of this study. It is also possible that you will continue to receive the study
drug as part of an extension study, or from a government-sponsored or private health program.
It is also possible that you and/or your insurance provider will have to pay for drugs after
they become commercially available if you and your doctor wish to continue them. The study
doctor will tell you more if any of these things happen.

End-of-Treatment Visit:

About 14 days after your last dose of the study drugs, you will return to the clinic for an
end-of-treatment visit. At this visit:

- You will have a physical exam.

- Blood (about 4 teaspoons) and urine will be collected for routine and biomarker testing.
This blood will also be used to check your liver function, and PSA and testosterone
levels.

- You will have a bone scan and a MRI or CT scan to check the status of the disease.

- A bone marrow biopsy and aspiration will be collected for biomarker testing.

About 30 days after your last dose of the study drug, you will be asked how you are doing. If
you cannot return to the clinic, one of the study staff members will call you to check on
you. This call should last about 5-10 minutes.

Long-Term Follow-Up:

A member of the study staff will check up on you to ask how you are doing every 6 months
after your last dose of the study drugs. This could be either a phone call or a review of
your medical and/or other records. If you are contacted by phone, the call will only last a
few minutes.

Inclusion Criteria:

1. Willing and able to provide written informed consent.

2. Male aged 18 years and above.

3. Histologically or cytologically confirmed adenocarcinoma of the prostate.

4. Presence of metastatic disease documented on imaging studies (bone scan, CT and/or MRI
scans).

5. Patients must have documented evidence of progressive disease as defined by any of the
following: a) PSA progression: minimum of 2 rising values (3 measurements) obtained a
minimum of 7 days apart with the last result being at least >/= 1.0 ng/mL; b) New or
increasing non-bone disease (RECIST 1.1 criteria); c) Positive bone scan with 2 or
more new lesions (PCWG3).

6. Surgically or ongoing medically castrated, with baseline testosterone levels of ng/dL (
7. Eastern Cooperative Oncology Group (ECOG) Performance Status of
8. Hemoglobin >/= 7.5 g/dL in the presence of bone marrow involvement independent of
transfusion and/or growth factors within 3 months prior to enrollment.

9. Platelet count >/= 100,000/uL independent of transfusion and or growth factors within
3 months prior to enrollment.

10. Serum albumin >/= 3.0g/dL.

11. Medications known to lower the seizure threshold must be discontinued or substituted
at least 4 weeks prior to study entry.

12. Absolute neutrophil count (ANC) >/= 1,500/mm3.

13. Calculated creatinine clearance (Cockcroft-Gault Equation) >/= 40 mL/min.

14. Serum potassium >/= Institutional Lower Limit of Normal (ILLN).

15. Serum magnesium >/= ILLN.

16. Serum bilirubin < 1.5 x Institutional Upper Limit of Normal (IULN) (except for
patients with known Gilbert's disease).

17. Serum AST or ALT < 2.5 x IULN for patients without liver metastases. For patients with
liver metastases AST or ALT < 5 x IULN is allowed.

18. Able to swallow study drugs whole as a tablet/capsule.

19. Male subject with a female partner of childbearing potential or pregnant must agree to
use two acceptable methods of contraception and not to donate sperm from time of
Screening until 3 months after the last dose of study treatments.

20. Patients must agree to tissue collection for correlative studies (including
participation in PA13-0291 and PA13-0247 for MD Anderson participants) at the
specified timepoints.

Exclusion Criteria:

1. Any prior treatment with: Ipilimumab

2. Treatment within 28 days of Cycle1 Day1: Any other systemic therapy for prostate
cancer (with the exception of LHRH agonists and LHRH antagonists for testosterone
suppression, Sipuleucel-T and bisphosphonates and RANK-ligand inhibitors for bone
metastases which are allowed). --Any other investigational product --Any medications
listed in Appendix H.

3. Treatment within 12 months of Cycle 1 Day 1 with any Cyp17-lyase inhibitor, any 2nd
generation AR antagonist (e.g. enzalutamide), cabazitaxel or carboplatin.

4. Patients treated with any Cyp17-lyase inhibitor, any 2nd generation AR antagonist
(e.g. enzalutamide), cabazitaxel or carboplatin whose disease progressed while on
treatment or within 3 months of its discontinuation. Patients who have received any of
these treatments more than 12 months from study entry and whose disease did not
progress while on treatment or within 3 months of its discontinuation are allowed on
study.

5. Patients whose disease is refractory (defined as evidence of disease progression while
on drug or within 3 months of its discontinuation) to more than 2 lines of
chemotherapy. Any number of chemotherapies to which the patient's disease is not
refractory are allowed, as long as time on treatment did not exceed 6 months (counted
from day 1 of cycle 1 to day 1 of the last cycle of treatment).

6. Flutamide (Eulexin) treatment within 4 weeks of Cycle 1, Day 1 and Bicalutamide
(Casodex) or nilutamide (Nilandron) within 6 weeks of Cycle 1 Day 1 (Exceptions: if
progression is documented prior to this time interval, or if patient is deemed by the
treating physician to be highly unlikely to respond to AR inhibitor withdrawal (e.g.
if PSA did not decline for >/= 3 months in response to AR inhibitor given as a second
line or later intervention, or if patient has symptoms attributed to disease
progression) only a 3 day washout prior to Cycle 1, Day 1 will be required for any of
them.

7. Radiation therapy for treatment of the primary tumor within 6 weeks of Cycle 1, Day 1.
Patients who have received palliative radiation to a single site and recovered are
eligible.

8. Any chronic medical condition requiring a higher dose of corticosteroid than 10mg
prednisone/prednisolone daily. Use of inhaled, intranasal, intra-articular and topical
steroids is acceptable, as is a short course (i.e. prevent a reaction to the IV contrast used for CT scans.

9. Active infection (requiring oral or IV antibiotics or antiviral therapy) or other
medical condition that would make prednisone/prednisolone (corticosteroid) use
contraindicated. Known history of testing positive for human immunodeficiency virus
(HIV) or known acquired immunodeficiency syndrome (AIDS).

10. A malignancy [other than the one treated in this study] which required radiotherapy or
systemic treatment within the past 5 years, or has a >/= 30% probability of recurrence
within 24 months (except for non-melanoma skin cancer or Ta urothelial carcinomas).

11. Uncontrolled hypertension (systolic BP >/= 140 mmHg or diastolic BP >/= 90 mmHg).
Patients with a history of hypertension are allowed provided blood pressure is
controlled by anti-hypertensive treatment.

12. Prolonged QTc interval on pre-entry electrocardiogram (>/= 450 msec).

13. Known active or symptomatic viral hepatitis or chronic liver disease.

14. Clinically significant heart disease as evidenced by myocardial infarction, or
arterial thrombotic events in the past 6 months, severe or unstable angina, history of
clinically significant ventricular arrhythmias (such as ventricular tachycardia,
ventricular fibrillation, or Torsade de pointes), New York Heart Association (NYHA)
Class III-IV heart disease or cardiac ejection fraction measurement of < 40% at
baseline.

15. Autoimmune disease: Patients with a history of inflammatory bowel disease (including
Crohn's disease and ulcerative colitis) and autoimmune disorders such as rheumatoid
arthritis, autoimmune thyroiditis, autoimmune hepatitis, systemic progressive
sclerosis [scleroderma and variants], Systemic Lupus Erythematosus, autoimmune
vasculitis [e.g., Wegener's Granulomatosis] or autoimmune neuropathies (such as
Guillain-Barre syndrome) are excluded from this study. Vitiligo and adequately
controlled endocrine deficiencies such as hypothyroidism are not exclusionary.

16. Patients who have had a history of illness which put them at current risk for bowel
perforation such as acute diverticulitis, intra-abdominal abscess, GI obstruction and
abdominal carcinomatosis

17. History of seizure or known condition that may pre-dispose to seizure (including but
not limited to prior stroke or, loss of consciousness within 1 year prior to
randomization, brain arteriovenous malformation; or intracranial masses such as
schwannomas and meningiomas that are causing edema or mass effect).

18. Gastrointestinal disorder affecting absorption.

19. Any underlying medical or psychiatric condition, which in the opinion of the
Investigator, will make the administration of study drug hazardous or obscure the
interpretation of adverse events.

20. Untreated symptomatic spinal cord compressions.

21. Prisoners or subjects who are involuntarily incarcerated.

22. Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness.