SUMMARY OF CHANGES
Revision # 1, March 30, 2004

RTOG P-0014, “A Phase III Randomized Study of Patients with High Risk, Hormone-Naïve Prostate Cancer: Androgen Blockade with 4 Cycles of Immediate Chemotherapy versus Androgen Blockade with Delayed Chemotherapy”

Study Chair: Kenneth James Pienta M.D., (734) 647-3421, FAX (734) 647-9480, kpienta@umich.edu

IRB Review Requirements:
(   ) Full board review required
( X ) Expedited review allowed, however, site IRB requirements take precedence
(   ) No review required


RTOG P-0014 has been revised follows:

Schema: In Arm 1, “2 weeks” was changed to “4 weeks” and “leuprolide or goserelin” was changed to “with LHRH agonists.” In Arm 2, “8 months” was changed to “32 weeks.” This change to specify 32 weeks was made throughout the protocol for clarity and consistency. Under Original Combined Gleason, # 1 was changed from 7 to 6, # 2 was changed from 8-10 to 7, and # 3 was added as 8-10.

Schema Footnote: Separated into Arm 1 and Arm 2 for clarity.

**AB:
Arm 1: Androgen was capitalized. “leuprolide or goserelin” changed to “LHRH agonists” in the first sentence. New text was added: “Patients may receive complete androgen blockade or monotherapy. Regimen choice and choice of complete androgen blockade vs. one-month nonsteroidal antiandrogen blockade is at discretion of enrolling physician.”

Arm 2: “at time of failure of hormonal therapy” was added after “chemotherapy”at the end of the first sentence.

*Chemotherapy:
Arm 1: “2 weeks” was changed to “4 weeks” and “with LHRH agonists” was added at the end of the first sentence. New text was added: “Once a chemotherapy regimen is chosen for a patient on Arm 1, that regimen may be reduced/stopped for toxicity; however, patients may not be changed from regimen to regimen in Arm 1 during the initial chemotherapy. Each investigator or Oncology Group may choose the regimen from the list included within the protocol for each patient. A patient may receive further therapy with protocol or non-protocol chemotherapy at physician discretion when a patient progresses on Arm 1.”

Arm 2: “8 months” was changed to “32 weeks.” A new second sentence was added: “There is no PSA value minimum for initiation of chemotherapy in Arm 2.” Other changes “or Oncology Group” added to third sentence to reflect addition of other cooperative groups, “from the list included with the protocol” inserted into the third sentence after “regimen”. The word “Note” and its first sentence was deleted; the second sentence was rewritten as “A patient may receive non-protocol chemotherapy regimens…if a patient fails the first protocol chemotherapy regimen….” for clarification.

Two additional regimens, # 5, # 6, and # 7 “Future regimens may be added that have demonstrated activity in Phase II clinical trials and are approved by the GU committee of RTOG.” were added to the list of choices to reflect changes made to Section 7.0 of the protocol.

Schema Eligibility: In second bullet, “8 months” was changed to “32 weeks,” “or Gleason 6 with capsular penetration or positive seminal vesicles or lymph nodes” was added to the first sentence; “To be eligible, the patient must have a PSA of > 2 at the time of randomization. Values of less than 2 can be used to calculate the doubling time. The PSA doubling time is calculated in the following manner: Doubling time in weeks = amount of time between PSA values in weeks/[change in PSA/1st value]. If this number is less than or equal to 32 weeks, the patient meets this criteria. [5 examples of doubling time are given here]. The third bullet, “No clinical or radiographic evidence of disease” was added for consistency with Section 3.2.8. In the seventh bullet, “8 months” was changed to “32 weeks.” In the second to last bullet, “non-melanomatous” was deleted for consistency with Eligibility Checklist page 1, Question #13 and Section 3.2.4.

ELIGIBILITY CHECKLIST:
Page 1: Question # 2, “or Gleason 6 with capsular penetration or positive seminal vesicles or lymph nodes” was added to the end for consistency. Questions # 3 and # 11, “8 months” was changed to “32 weeks.” Question # 10, 3.18 was deleted and 3.1.11 was added.

Page 2: Question # 5, changed from “Patient’s Name” to “Patient’s Initials (First, Middle, Last) If no middle, use hyphen” according to RTOG standards; in Question # 18 “6 vs.” was added; a new Question # 20, was added; old Questions # 20 and 21 were renumbered as Questions # 21 and # 22.

Section 1.0: A sentence was added at the end of paragraph eleven. In paragraph twelve, “or phase III” and “demonstrable” were added to the third sentence and an additional sentence was added to the end of the paragraph. In the table following paragraph twelve, two regimens of taxotere and the corresponding footnotes “m” and “n” were added.

Section 2.2.1 and Section 13.1.2 first bullet: This was revised as “ Biochemical control; PSA failure is defined as a PSA doubling time < 32 weeks.

Section 2.2.2 and Section 13.1.2 second bullet: “or a PSA doubling time < 32 weeks” was added to end of first sentence.

Section 3.1.2: “or Gleason 6 with capsular penetration or positive seminal vesicles or lymph nodes” was added because the ultimate reason for patients to be eligible for this trial is rapid doubling time. Patients with Gleason 6 with capsular penetration or positive seminal vesicles or lymph nodes represent a group that is at high risk of dying of their disease and should be eligible for this trial in addition to those with higher Gleason scores.

Section 3.1.3: “8 months” was changed to “< 32 weeks” here and in Section 3.1.6; “The PSA doubling time is calculated in the following manner:” was added and five examples of doubling time calculations are given consistent with those in Eligibility.

Sections 3.1.9, 3.1.10, 3.1.11: “within 4 weeks prior to randomization” was moved from the end of the sentence to before the colon for clarity.

Sections 3.1.13, 3.1.14, 3.1.15, 4.4, 4.5, 4.6: “6 weeks” was changed to “8 weeks” prior to randomization. This will increase the ability to accrue patients to this trial without compromising the characteristics of the patients enrolled in the trial.

Section 3.2.8: Added “Clinical or radiographic evidence of disease.”

Section 4.0: “2 weeks” was changed to “4 weeks” for protocol treatment to begin after registration. This will increase the ability to accrue patients to this trial without compromising the characteristics of the patients enrolled in the trial.

Section 5.1: “or via the RTOG website 24 hours 7 days a week” was added to the second sentence.

Section 7.1.1: This section was separated into Arm 1 and Arm 2 for clarity.

Arm 1: In the first sentence, “leuprolide or goserelin” was changed to “LHRH agonists.” Three sentences were added to the second paragraph.

Arm 2: New section added.

Sections 7.2, 7.3: These sections were revised from specific agents, Lupron (leuprolide) and Zoladex (goserelin), to non-specific use of LHRH analogs in order to allow for the use of all four FDA approved compounds regardless of the manufacturer. Sections 7.2.1, 7.2.2, 7.2.3, 7.2.4, 7.2.5and 7.2.6 were rewritten. The entire Section 7.3 (7.3.1 through 7.3.6) was deleted and subsequent Sections 7.4 through 7.16 were renumbered as Sections 7.3 through 7.15. All cross-REFERENCES within the text of the protocol were changed accordingly.

Section 7.4.6 (old 7.5.6): “and RTOG Headquarters must be notified.” was deleted at the end of the section.

Section 7.5.1 (old 7.6.1): This section was separated into Arm 1 and Arm 2.

Arm 1: In the first sentence, “2” was changed to “4” weeks. The rest of the section was rewritten.

Note: The first sentence was deleted and “protocol” was inserted before “chemotherapy” in the now first sentence and “non-protocol” was inserted before “chemotherapy” in the now second sentence

Arm 2: in three places, “8 months” was changed to “32 weeks” for consistency. A new second sentence was added: “There is no minimum PSA requirement to initiate chemotherapy in Arm 2.”

Section 7.14: The regimens 1-7 were all listed here including the three new ones for ease of reference.

Sections 7.14.1 through 7.14.1.6/ Sections 7.14.2.1 through 7.14.2.6/ Sections 7.14.3.1 through 7.14.3.5/Sections 7.14.4.1 through 7.14.4.6: The information in these sections was reorganized for uniformity as follows: Sections 7.14.1.3 and 7.14.4.3: In the second sentence, “for docetaxel” was inserted after “modifications” for clarity.

Section 7.14.2.1: A second sentence was added, “One cycle equals 6 continuous weeks followed by 2 weeks rest” for clarity.

Section 7.14.2.3: In second sentence, “for paclitaxel” was inserted after “modifications”; in the fourth sentence, > was changed to > in two places for clarity.

Section 7.14.3.1: “with ketoconazole” was added to hydrocortisone for clarification.

Section 7.14.3.3: In the third sentence, “for adriamycin and vinblastine” was inserted after “modifications” for clarity.

Section 7.14.4.1: A second sentence was added, “A cycle is 3 weeks followed by one week rest.” for clarity.

Sections 7.14.5, 7.14.6, and 7.14.7: New Section 7.14.5 Docetaxel (D), Section 7.14.6 Weekly docetaxel (WD), and Section 7.14.7 possible future regimens were added.

Section 7.15.3: Updated the fax number for RTOG.

Section 11.1: “Note of bisphosphonate use” was added “Every 3 months.” Added CBC, Platelets to be done “Every 3 months. Since PSA, Serum ALT etc parameter and CBC, Platelets parameter were deleted from being done “Every two months during AB,” the column was eliminated in the table. Footnote b was changed from 6 to 8 weeks. The superscript “b” was deleted from Bone Scan, Pelvic CT…assessment, and Chest X-ray and added to the “Xs” for these assessments in the Pre-therapy column.

Section 11.2: “Note of bisphosphonate use” was added “Prior to each cycle of chemotherapy”. “i.e., if deemed necessary by the physician to evaluate the patient who has new symptoms” was added to footnote c. Footnote e was added and indicated for PSA “After Chemotherapy.”

Section 11.4.1: The first sentence was changed to read: “PSA failure is defined as a PSA doubling time < 32 weeks.”

Sections 11.4.2.2, 11.4.2.3, 11.4.2.4, 11.4.2.5.1, and 11.4.2.6: These were deleted.

Section 11.4.2.2(old 11.4.2.5): This is section was renumbered.

Section 11.4.2.3(old 11.4.2.7): This section was renumbered and was revised as “An increase in the number of lesions on bone scan. Or a PSA doubling time of < 32 weeks.

Section 11.5.1: The second sentence was revised as “PSA failure is defined as a PSA doubling time < 32 weeks. The last sentence was deleted.

Section 11.5.2: “or a PSA doubling time < 32 weeks” was added to the end of the first sentence.

Section 13.2.1: The references were renumbered starting in this section from # 30-37 corresponding to the Reference list where reference # 30 was deleted. “6” was added to the Gleason score in the parentheses in the third line.

Section 13.2.2.1: This new section was added addressing sample size.

References: Two new references # 38 and # 39 were added.

Appendix I:
Under What Is Involved In The Study? Treatment 1, in the first sentence of the second paragraph “ injections of a hormone, either Zoladex or Lupron” was replaced by “You will receive one of the commercial hormone treatments currently being used for your condition.” In the third paragraph, the first two sentences were deleted and a new sentence was added: “The form of the commercial hormone treatment you will receive depends upon which one your doctor chooses to give you.” The last sentence of the last paragraph was changed to “ The length of time that chemotherapy will continue depends upon which treatment you are given. This change was made also in the last sentence of the second paragraph for Treatment 2.

Under How Long Will I Be In The Study? the first paragraph, the second sentence was revised for consistency with the rest of the protocol.

Under What Are The Risks Of The Study? “LHRH Agonists such as leuprolide, goserelin, buserelin, triptorelin” was added to the heading “Hormones:” The following sections were deleted: “Less Likely, but Serious Zoladex specific” and “Less Likely, but Serious Lupron specific” for consistency with the revision from specific agents, Lupron and Zoladex to non-specific use of LHRH analogs.

Under Where Can I Get More Information? the websites were updated.

An updated protocol is available (no password required) on the RTOG website: http://www.rtog.org/





SUMMARY OF CHANGES
Update Date: May 19, 2003

RTOG P-0014, “A Phase III Randomized Study of Patients with High Risk, Hormone-Naïve Prostate Cancer: Androgen Blockade with 4 Cycles of Immediate Chemotherapy versus Androgen Blockade with Delayed Chemotherapy”

Study Chair: Kenneth James Pienta M.D., (734) 647-3421, FAX (734) 647-9480, kpienta@umich.edu


RTOG P-0014 has been updated as follows:

Title Page — Added Study Co-chairs for CALGB and SWOG.

NOTE: This is an editorial/administrative change to the protocol. NCI now requires that these changes be documented on the protocol title page with the date of the update noted as “Update Date”.

An updated protocol is available (no password required) on the RTOG website: http://www.rtog.org/